19-38915670-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.58

Variant links:

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 links:

ENSG00000269547 (HGNC:):

ENSG00000269547 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SARS2	NM_017827.4 link	c.1493T>C	p.Leu498Pro	missense_variant	Exon 16 of 16	ENST00000221431.11	NP_060297.1	Q9NP81-1
SARS2	NM_001145901.2 link	c.1499T>C	p.Leu500Pro	missense_variant	Exon 17 of 17		NP_001139373.1	Q9NP81-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SARS2	ENST00000221431.11 link	c.1493T>C	p.Leu498Pro	missense_variant	Exon 16 of 16	1	NM_017827.4	ENSP00000221431.6		Q9NP81-1
ENSG00000269547	ENST00000599996.1 link	c.1700T>C	p.Leu567Pro	missense_variant	Exon 20 of 20	2		ENSP00000472465.1		M0R2C6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

250426

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135352

show subpopulations

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:

AN:

1461072

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726738

show subpopulations

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.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperuricemia, pulmonary hypertension, renal failure, alkalosis syndrome

Uncertain:1

May 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). This variant is present in population databases (rs752525142, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with SARS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1900680). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

T;.;T;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.95

M_CAP

Pathogenic

0.36

MetaRNN

Uncertain

0.67

D;D;D;D;D

MetaSVM

Uncertain

0.010

MutationAssessor

Benign

1.5

L;.;.;.;.

PrimateAI

Uncertain

0.60

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over