rs201358272

Variant names:

• chr7-30632247-C-G
• rs201358272
• NM_002047.4:c.1904C>G

Your query was ambiguous. Multiple possible variants found:

• chr7-30632247-C-G
• chr7-30632247-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002047.4(GARS1):​c.1904C>G​(p.Ser635Trp) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S635L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GARS1 NM_002047.4 missense, splice_region
• Scores: Splicing: ADA: 0.8912
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 25 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GARS1	NM_002047.4	c.1904C>G	p.Ser635Trp	missense_variant, splice_region_variant	Exon 16 of 17	ENST00000389266.8	NP_002038.2
GARS1	NM_001316772.1	c.1742C>G	p.Ser581Trp	missense_variant, splice_region_variant	Exon 16 of 17		NP_001303701.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GARS1	ENST00000389266.8	c.1904C>G	p.Ser635Trp	missense_variant, splice_region_variant	Exon 16 of 17	1	NM_002047.4	ENSP00000373918.3
GARS1	ENST00000675651.1	c.1922C>G	p.Ala641Gly	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502513.1
GARS1	ENST00000675810.1	c.1802C>G	p.Ser601Trp	missense_variant, splice_region_variant	Exon 15 of 16			ENSP00000502743.1
GARS1	ENST00000675693.1	c.1736C>G	p.Ser579Trp	missense_variant, splice_region_variant	Exon 17 of 18			ENSP00000502174.1
GARS1	ENST00000675051.1	c.1703C>G	p.Ser568Trp	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502296.1
GARS1	ENST00000674815.1	c.1535C>G	p.Ser512Trp	missense_variant, splice_region_variant	Exon 16 of 17			ENSP00000502799.1
GARS1	ENST00000674851.1	c.1535C>G	p.Ser512Trp	missense_variant, splice_region_variant	Exon 17 of 18			ENSP00000502451.1
GARS1	ENST00000444666.6	n.*325C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1618C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1709C>G		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1242C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*177C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1774C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*83C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1846C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 18 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*849C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1355C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1193C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1336C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000501980.1
GARS1	ENST00000676403.1	n.1810C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 15 of 16			ENSP00000502681.1
GARS1	ENST00000444666.6	n.*325C>G		3_prime_UTR_variant	Exon 17 of 18	3		ENSP00000415447.2
GARS1	ENST00000674616.1	n.*1618C>G		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502408.1
GARS1	ENST00000674643.1	n.*1709C>G		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501636.1
GARS1	ENST00000674737.1	n.*1242C>G		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502464.1
GARS1	ENST00000674807.1	n.*177C>G		3_prime_UTR_variant	Exon 15 of 16			ENSP00000502814.1
GARS1	ENST00000675529.1	n.*1774C>G		3_prime_UTR_variant	Exon 17 of 18			ENSP00000501655.1
GARS1	ENST00000675859.1	n.*83C>G		3_prime_UTR_variant	Exon 14 of 15			ENSP00000502033.1
GARS1	ENST00000676088.1	n.*1846C>G		3_prime_UTR_variant	Exon 18 of 19			ENSP00000501884.1
GARS1	ENST00000676140.1	n.*849C>G		3_prime_UTR_variant	Exon 16 of 17			ENSP00000502571.1
GARS1	ENST00000676164.1	n.*1355C>G		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501986.1
GARS1	ENST00000676210.1	n.*1193C>G		3_prime_UTR_variant	Exon 17 of 18			ENSP00000502373.1
GARS1	ENST00000676259.1	n.*1336C>G		3_prime_UTR_variant	Exon 16 of 17			ENSP00000501980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249178 AF XY: 0.00000740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 14, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S635W variant (also known as c.1904C>G) is located in coding exon 16 of the GARS gene. The serine at codon 635 is replaced by tryptophan, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 16. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.65	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.54	D
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.69		Loss of disorder (P = 0.0024);
MVP		0.87
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.92
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.64
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: rs201358272; hg19: chr7-30671863;