19-38915660-G-C

Variant names:

• chr19-38915660-G-C
• rs562766344
• NM_017827.4:c.1503C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017827.4(SARS2):​c.1503C>G​(p.Ile501Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I501V) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: SARS2 NM_017827.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644
• Publications: 2 publications found

Genes affected

SARS2 (HGNC:17697): (seryl-tRNA synthetase 2, mitochondrial) This gene encodes the mitochondrial seryl-tRNA synthethase precursor, a member of the class II tRNA synthetase family. The mature enzyme catalyzes the ligation of Serine to tRNA(Ser) and participates in the biosynthesis of selenocysteinyl-tRNA(sec) in mitochondria. The enzyme contains an N-terminal tRNA binding domain and a core catalytic domain. It functions in a homodimeric form, which is stabilized by tRNA binding. This gene is regulated by a bidirectional promoter that also controls the expression of mitochondrial ribosomal protein S12. Both genes are within the critical interval for the autosomal dominant deafness locus DFNA4 and might be linked to this disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Mar 2009]

SARS2 Gene-Disease associations (from GenCC):

• hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, PanelApp Australia, Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ENSG00000269547 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41588295).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017827.4. 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
	SARS2	NM_017827.4	MANE Select	c.1503C>G	p.Ile501Met	missense	Exon 16 of 16	NP_060297.1	Q9NP81-1
	SARS2	NM_001145901.2		c.1509C>G	p.Ile503Met	missense	Exon 17 of 17	NP_001139373.1	Q9NP81-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SARS2	ENST00000221431.11	TSL:1 MANE Select	c.1503C>G	p.Ile501Met	missense	Exon 16 of 16	ENSP00000221431.6	Q9NP81-1
	ENSG00000269547	ENST00000599996.1	TSL:2	c.1710C>G	p.Ile570Met	missense	Exon 20 of 20	ENSP00000472465.1	M0R2C6
	SARS2	ENST00000598831.6	TSL:5	c.1503C>G	p.Ile501Met	missense	Exon 16 of 17	ENSP00000468865.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152198 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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250404 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74344

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.079	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.64
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.20
Sift	Benign	0.049	D
Sift4G	Benign	0.075	T
Polyphen		0.31	B
Vest4		0.61
MutPred		0.30		Loss of catalytic residue at P503 (P = 0.0307)
MVP		0.83
MPC		0.89
ClinPred		0.72	D
GERP RS		2.6
Varity_R		0.18
gMVP		0.73
Mutation Taster		=76/24	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: rs562766344; hg19: chr19-39406300;