19-38915670-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_017827.4(SARS2):c.1493T>C(p.Leu498Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000013 in 1,461,072 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SARS2 NM_017827.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000013 (19/1461072) while in subpopulation AMR AF= 0.000403 (18/44698). AF 95% confidence interval is 0.00026. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SARS2	NM_017827.4	c.1493T>C	p.Leu498Pro	missense_variant	16/16	ENST00000221431.11
SARS2	NM_001145901.2	c.1499T>C	p.Leu500Pro	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SARS2	ENST00000221431.11	c.1493T>C	p.Leu498Pro	missense_variant	16/16	1	NM_017827.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000599 AC: 15 AN: 250426 Hom.: 0 AF XY: 0.0000591 AC XY: 8 AN XY: 135352

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461072 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 726738

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 28, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SARS2-related conditions. This variant is present in population databases (rs752525142, gnomAD 0.04%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 498 of the SARS2 protein (p.Leu498Pro). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;.;T;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Uncertain	0.010	D
MutationAssessor	Benign	1.5	L;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D;.;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;.;.;.;.
Sift4G	Benign	0.068	T;T;T;D;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.73
MutPred		0.52		Gain of catalytic residue at P497 (P = 0.0107);.;Gain of catalytic residue at P497 (P = 0.0107);.;.;
MVP		0.98
MPC		1.3
ClinPred		0.39	T
GERP RS		4.9
Varity_R		0.54
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs752525142; hg19: chr19-39406310;