7-30598875-G-A

Position:

• chr7-30598875-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_002047.4(GARS1):​c.302G>A​(p.Arg101His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000271 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: 9.10

Genes affected

GARS1 (HGNC:4162): (glycyl-tRNA synthetase 1) This gene encodes glycyl-tRNA synthetase, one of the aminoacyl-tRNA synthetases that charge tRNAs with their cognate amino acids. The encoded enzyme is an (alpha)2 dimer which belongs to the class II family of tRNA synthetases. It has been shown to be a target of autoantibodies in the human autoimmune diseases, polymyositis or dermatomyositis. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

GARS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000236 (36/152300) while in subpopulation AMR AF= 0.000588 (9/15304). AF 95% confidence interval is 0.000306. There are 0 homozygotes in gnomad4. There are 17 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 36 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.302G>A	p.Arg101His	missense_variant	2/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.140G>A	p.Arg47His	missense_variant	2/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.302G>A	p.Arg101His	missense_variant	2/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.302G>A	p.Arg101His	missense_variant	2/17			ENSP00000502513.1
GARS1	ENST00000675693.1	c.134G>A	p.Arg45His	missense_variant	3/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.101G>A	p.Arg34His	missense_variant	2/17			ENSP00000502296.1
GARS1	ENST00000674815	c.-68G>A		5_prime_UTR_variant	2/17			ENSP00000502799.1
GARS1	ENST00000674851	c.-68G>A		5_prime_UTR_variant	3/18			ENSP00000502451.1
GARS1	ENST00000675810.1	c.223-1072G>A		intron_variant				ENSP00000502743.1
GARS1	ENST00000444666.6	n.302G>A		non_coding_transcript_exon_variant	2/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.302G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.302G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.302G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.302G>A		non_coding_transcript_exon_variant	2/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*172G>A		non_coding_transcript_exon_variant	3/18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.302G>A		non_coding_transcript_exon_variant	2/15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*172G>A		non_coding_transcript_exon_variant	3/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.302G>A		non_coding_transcript_exon_variant	2/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.302G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.302G>A		non_coding_transcript_exon_variant	2/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.302G>A		non_coding_transcript_exon_variant	2/17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.302G>A		non_coding_transcript_exon_variant	2/16			ENSP00000502681.1
GARS1	ENST00000675529.1	n.*172G>A		3_prime_UTR_variant	3/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*172G>A		3_prime_UTR_variant	3/19			ENSP00000501884.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000345 AC: 86 AN: 249370 Hom.: 0 AF XY: 0.000355 AC XY: 48 AN XY: 135338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000592

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000274 AC: 401 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.000267 AC XY: 194 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000324

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74476

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000460 Hom.: 0

Bravo AF: 0.000280

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000381 AC: 46

EpiCase AF: 0.000491

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GARS1: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2022	Reported as a variant of unknown significance in individuals tested by an outside laboratory suspected of having Charcot-Marie-Tooth disease (DiVincenzo et al., 2014; Nam et al., 2021; Volodarsky et al., 2021); Identified previously in the heterozygous state in two individuals with neuropathy (Antoniadi et al., 2015; Apellniz-Ruiz et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27582484, 28166811, 34813128, 32028661, 34426522, 29520015, 32376792, 25614874, 26392352) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2021	- -

not specified Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2024	Variant summary: GARS1 c.302G>A (p.Arg101His) results in a non-conservative amino acid change located in the WHEP-TRS domain (IPR000738) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 280760 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.302G>A has been reported in the literature in individuals affected with neuropathy, CMT, or ALS without strong evidence of causality (e.g. Antoniadi_2015, Apellaniz-Ruiz_2017, Pensato_2020, Volodarsky_2021, Nam_2022). These reports do not provide unequivocal conclusions about association of the variant with GARS1-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant does not result in aberrant GlyRS-HDAC6 interaction (Mo_2018). The following publications have been ascertained in the context of this evaluation (PMID: 26392352, 27582484, 29520015, 32028661, 32376792, 34813128). ClinVar contains an entry for this variant (Variation ID: 245685). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Distal spinal muscular atrophy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Charcot-Marie-Tooth disease type 2D Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Neuronopathy, distal hereditary motor, type 5A Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.70	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.4	D
REVEL	Uncertain	0.34
Sift	Benign	0.053	T
Sift4G	Benign	0.35	T
Polyphen		1.0	D
Vest4		0.88
MVP		0.49
MPC		0.57
ClinPred		0.47	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs200887429; hg19: chr7-30638491; COSMIC: COSV66828540; COSMIC: COSV66828540;