7-30595045-C-G

Variant names:

• chr7-30595045-C-G
• rs1049402
• NM_002047.4:c.124C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002047.4(GARS1):​c.124C>G​(p.Pro42Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 1,559,586 control chromosomes in the GnomAD database, including 446,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P42T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.70 (38061 hom., cov: 32)
  • Exomes 𝑓: 0.76 (407962 hom.)
• Consequence: GARS1 NM_002047.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: -0.799
• Publications: 49 publications found

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-DT (HGNC:48951): (GARS1 divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.2903471E-6).
• BP6: Variant 7-30595045-C-G is Benign according to our data. Variant chr7-30595045-C-G is described in ClinVar as Benign. ClinVar VariationId is 258532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002047.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.124C>G	p.Pro42Ala	missense	Exon 1 of 17	NP_002038.2	P41250-1
	GARS1	NM_001316772.1		c.-39C>G		5_prime_UTR	Exon 1 of 17	NP_001303701.1	P41250-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.124C>G	p.Pro42Ala	missense	Exon 1 of 17	ENSP00000373918.3	P41250-1
	GARS1	ENST00000675651.1		c.124C>G	p.Pro42Ala	missense	Exon 1 of 17	ENSP00000502513.1	A0A6Q8PGZ8
	GARS1	ENST00000675810.1		c.124C>G	p.Pro42Ala	missense	Exon 1 of 16	ENSP00000502743.1	A0A6Q8PHH9

Frequencies

GnomAD3 genomes AF: 0.701 AC: 106602 AN: 151984 Hom.: 38038 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.824

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.629

Gnomad FIN AF: 0.719

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.778

Gnomad OTH AF: 0.739

GnomAD2 exomes AF: 0.706 AC: 118929 AN: 168478 AF XY: 0.706

Gnomad AFR exome AF: 0.546

Gnomad AMR exome AF: 0.663

Gnomad ASJ exome AF: 0.820

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.705

Gnomad NFE exome AF: 0.770

Gnomad OTH exome AF: 0.749

GnomAD4 exome AF: 0.759 AC: 1067954 AN: 1407484 Hom.: 407962 Cov.: 71 AF XY: 0.755 AC XY: 526112 AN XY: 696912

African (AFR) AF: 0.559 AC: 18214 AN: 32594

American (AMR) AF: 0.665 AC: 26023 AN: 39104

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 20868 AN: 25382

East Asian (EAS) AF: 0.641 AC: 24008 AN: 37448

South Asian (SAS) AF: 0.621 AC: 50450 AN: 81214

European-Finnish (FIN) AF: 0.715 AC: 25766 AN: 36028

Middle Eastern (MID) AF: 0.764 AC: 4212 AN: 5514

European-Non Finnish (NFE) AF: 0.783 AC: 854592 AN: 1091486

Other (OTH) AF: 0.746 AC: 43821 AN: 58714

GnomAD4 genome AF: 0.701 AC: 106665 AN: 152102 Hom.: 38061 Cov.: 32 AF XY: 0.696 AC XY: 51780 AN XY: 74370

African (AFR) AF: 0.571 AC: 23691 AN: 41476

American (AMR) AF: 0.697 AC: 10647 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.824 AC: 2860 AN: 3472

East Asian (EAS) AF: 0.660 AC: 3400 AN: 5148

South Asian (SAS) AF: 0.630 AC: 3039 AN: 4826

European-Finnish (FIN) AF: 0.719 AC: 7623 AN: 10596

Middle Eastern (MID) AF: 0.782 AC: 230 AN: 294

European-Non Finnish (NFE) AF: 0.778 AC: 52908 AN: 67986

Other (OTH) AF: 0.739 AC: 1561 AN: 2112

Alfa AF: 0.731 Hom.: 5135

Bravo AF: 0.696

TwinsUK AF: 0.787 AC: 2918

ALSPAC AF: 0.785 AC: 3024

ESP6500AA AF: 0.631 AC: 2445

ESP6500EA AF: 0.792 AC: 6367

ExAC AF: 0.658 AC: 73907

Asia WGS AF: 0.650 AC: 2263 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	Charcot-Marie-Tooth disease type 2D (3)
-	-	2	Neuronopathy, distal hereditary motor, type 5A (2)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Distal spinal muscular atrophy (1)
-	-	1	Spinal muscular atrophy, infantile, James type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.25
DANN	Benign	0.56
DEOGEN2	Benign	0.045	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.80
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.093
Sift	Benign	0.96	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.060
MPC		0.34
ClinPred		0.015	T
GERP RS		-6.6
PromoterAI		0.0026	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.025
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1049402; hg19: chr7-30634661; COSMIC: COSV66827983; COSMIC: COSV66827983;