chr7-30631467-T-C

Position:

• chr7-30631467-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002047.4(GARS1):​c.1829T>C​(p.Val610Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,372 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11495265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1829T>C	p.Val610Ala	missense_variant	15/17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1667T>C	p.Val556Ala	missense_variant	15/17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1829T>C	p.Val610Ala	missense_variant	15/17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1829T>C	p.Val610Ala	missense_variant	15/17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1727T>C	p.Val576Ala	missense_variant	14/16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1661T>C	p.Val554Ala	missense_variant	16/18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1628T>C	p.Val543Ala	missense_variant	15/17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1460T>C	p.Val487Ala	missense_variant	15/17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1460T>C	p.Val487Ala	missense_variant	16/18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*250T>C		non_coding_transcript_exon_variant	16/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1543T>C		non_coding_transcript_exon_variant	16/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*929T>C		non_coding_transcript_exon_variant	16/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1167T>C		non_coding_transcript_exon_variant	16/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*102T>C		non_coding_transcript_exon_variant	14/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1699T>C		non_coding_transcript_exon_variant	16/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1771T>C		non_coding_transcript_exon_variant	17/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*774T>C		non_coding_transcript_exon_variant	15/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1280T>C		non_coding_transcript_exon_variant	15/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1118T>C		non_coding_transcript_exon_variant	16/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1261T>C		non_coding_transcript_exon_variant	15/17			ENSP00000501980.1
GARS1	ENST00000444666.6	n.*250T>C		3_prime_UTR_variant	16/18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1543T>C		3_prime_UTR_variant	16/18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*929T>C		3_prime_UTR_variant	16/17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1167T>C		3_prime_UTR_variant	16/18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*102T>C		3_prime_UTR_variant	14/16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1699T>C		3_prime_UTR_variant	16/18			ENSP00000501655.1
GARS1	ENST00000676088.1	n.*1771T>C		3_prime_UTR_variant	17/19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*774T>C		3_prime_UTR_variant	15/17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1280T>C		3_prime_UTR_variant	15/17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1118T>C		3_prime_UTR_variant	16/18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1261T>C		3_prime_UTR_variant	15/17			ENSP00000501980.1
GARS1	ENST00000675859.1	n.*83-780T>C		intron_variant				ENSP00000502033.1
GARS1	ENST00000676403.1	n.1810-780T>C		intron_variant				ENSP00000502681.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461172 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74348

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 22, 2023

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 610 of the GARS protein (p.Val610Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 543201). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GARS protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.092
Sift	Benign	0.12	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.20
MutPred		0.46		Gain of sheet (P = 0.1208);
MVP		0.14
MPC		0.42
ClinPred		0.22	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.58

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: rs1554340666; hg19: chr7-30671083;