7-30615873-A-T

Variant names:

• chr7-30615873-A-T
• rs2527878
• NM_002047.4:c.1032-23A>T

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.1032-23A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0973 in 1,613,316 control chromosomes in the GnomAD database, including 8,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.10 (867 hom., cov: 33)
  • Exomes 𝑓: 0.097 (7956 hom.)
• Consequence: GARS1 NM_002047.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.148
• Publications: 11 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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2D

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• neuronopathy, distal hereditary motor, type 5A

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Laboratory for Molecular Medicine
• spinal muscular atrophy, infantile, James type

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-30615873-A-T is Benign according to our data. Variant chr7-30615873-A-T is described in ClinVar as Benign. ClinVar VariationId is 258531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	NM_002047.4	MANE Select	c.1032-23A>T		intron	N/A	NP_002038.2
	GARS1	NM_001316772.1		c.870-23A>T		intron	N/A	NP_001303701.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.1032-23A>T		intron	N/A	ENSP00000373918.3
	GARS1	ENST00000675651.1		c.1032-23A>T		intron	N/A	ENSP00000502513.1
	GARS1	ENST00000675810.1		c.930-23A>T		intron	N/A	ENSP00000502743.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15373 AN: 152088 Hom.: 865 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0931

Gnomad ASJ AF: 0.0939

Gnomad EAS AF: 0.180

Gnomad SAS AF: 0.197

Gnomad FIN AF: 0.0614

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0868

Gnomad OTH AF: 0.125

GnomAD2 exomes AF: 0.107 AC: 26655 AN: 249006 AF XY: 0.111

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0753

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.165

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0918

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.0969 AC: 141647 AN: 1461110 Hom.: 7956 Cov.: 31 AF XY: 0.0996 AC XY: 72413 AN XY: 726854

African (AFR) AF: 0.118 AC: 3942 AN: 33456

American (AMR) AF: 0.0767 AC: 3427 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2624 AN: 26128

East Asian (EAS) AF: 0.192 AC: 7621 AN: 39694

South Asian (SAS) AF: 0.187 AC: 16138 AN: 86176

European-Finnish (FIN) AF: 0.0623 AC: 3325 AN: 53390

Middle Eastern (MID) AF: 0.147 AC: 849 AN: 5758

European-Non Finnish (NFE) AF: 0.0874 AC: 97189 AN: 1111466

Other (OTH) AF: 0.108 AC: 6532 AN: 60352

GnomAD4 genome AF: 0.101 AC: 15382 AN: 152206 Hom.: 867 Cov.: 33 AF XY: 0.102 AC XY: 7585 AN XY: 74414

African (AFR) AF: 0.118 AC: 4883 AN: 41520

American (AMR) AF: 0.0929 AC: 1421 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 326 AN: 3472

East Asian (EAS) AF: 0.181 AC: 934 AN: 5174

South Asian (SAS) AF: 0.197 AC: 948 AN: 4822

European-Finnish (FIN) AF: 0.0614 AC: 651 AN: 10606

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0868 AC: 5903 AN: 68008

Other (OTH) AF: 0.129 AC: 271 AN: 2108

Alfa AF: 0.0949 Hom.: 141

Bravo AF: 0.105

Asia WGS AF: 0.214 AC: 743 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.45
PhyloP100		-0.15
La Branchor		0.71
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2527878; hg19: chr7-30655489; COSMIC: COSV66828074;