7-30594932-C-T

Variant names:

• chr7-30594932-C-T
• rs62636572
• ENST00000674815.1:c.-168C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001316772.1(GARS1):​c.-152C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0139 in 1,591,090 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (12 hom., cov: 33)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: GARS1 NM_001316772.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.13
• Publications: 8 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=0.0019283891).
• BP6: Variant 7-30594932-C-T is Benign according to our data. Variant chr7-30594932-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0124 (1882/152304) while in subpopulation AMR AF = 0.0169 (258/15296). AF 95% confidence interval is 0.0152. There are 12 homozygotes in GnomAd4. There are 1010 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1882 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316772.1. 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.11C>T	p.Pro4Leu	missense	Exon 1 of 17	NP_002038.2	P41250-1
	GARS1	NM_001316772.1		c.-152C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001303701.1	P41250-2
	GARS1	NM_001316772.1		c.-152C>T		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	ENST00000674815.1		c.-168C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000502799.1	A0A6Q8PGW4
	GARS1	ENST00000674851.1		c.-204C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	ENSP00000502451.1	A0A6Q8PGW4
	GARS1	ENST00000389266.8	TSL:1 MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 17	ENSP00000373918.3	P41250-1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1883 AN: 152186 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.0372

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0162

GnomAD2 exomes AF: 0.0116 AC: 2454 AN: 210896 AF XY: 0.0114

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0141 AC: 20291 AN: 1438786 Hom.: 172 Cov.: 30 AF XY: 0.0137 AC XY: 9830 AN XY: 715340

African (AFR) AF: 0.00216 AC: 72 AN: 33308

American (AMR) AF: 0.0124 AC: 541 AN: 43608

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 330 AN: 25884

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39334

South Asian (SAS) AF: 0.00360 AC: 304 AN: 84420

European-Finnish (FIN) AF: 0.0305 AC: 1220 AN: 39980

Middle Eastern (MID) AF: 0.0136 AC: 62 AN: 4554

European-Non Finnish (NFE) AF: 0.0153 AC: 16920 AN: 1107940

Other (OTH) AF: 0.0141 AC: 840 AN: 59758

GnomAD4 genome AF: 0.0124 AC: 1882 AN: 152304 Hom.: 12 Cov.: 33 AF XY: 0.0136 AC XY: 1010 AN XY: 74488

African (AFR) AF: 0.00245 AC: 102 AN: 41584

American (AMR) AF: 0.0169 AC: 258 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00310 AC: 15 AN: 4834

European-Finnish (FIN) AF: 0.0372 AC: 395 AN: 10622

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0152 AC: 1033 AN: 68006

Other (OTH) AF: 0.0161 AC: 34 AN: 2116

Alfa AF: 0.0135 Hom.: 27

Bravo AF: 0.0113

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00251 AC: 10

ESP6500EA AF: 0.0139 AC: 113

ExAC AF: 0.0104 AC: 1241

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Charcot-Marie-Tooth disease type 2D (1)
-	-	1	Distal spinal muscular atrophy (1)
-	-	1	Neuronopathy, distal hereditary motor, type 5A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.15
DANN	Benign	0.92
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.22
Sift	Benign	0.59	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.059
MPC		0.35
ClinPred		0.020	T
GERP RS		-1.4
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.019
gMVP		0.37
Mutation Taster		=100/0	polymorphism

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: rs62636572; hg19: chr7-30634548; COSMIC: COSV66829127; COSMIC: COSV66829127;