Variant 6-31815874-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005345.6(HSPA1A):c.118A>C(p.Ser40Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000187 in 1,605,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HSPA1A
NM_005345.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.75

Variant links:

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

HSPA1A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1A	NM_005345.6 linkuse as main transcript	c.118A>C	p.Ser40Arg	missense_variant	1/1	ENST00000375651.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1A	ENST00000375651.7 linkuse as main transcript	c.118A>C	p.Ser40Arg	missense_variant	1/1		NM_005345.6	P1	P0DMV8-1
HSPA1A	ENST00000608703.1 linkuse as main transcript	c.75+43A>C		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1457716

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724888

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

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:

0.0000166

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147998

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

71992

show subpopulations

Gnomad4 AFR

AF:

0.0000251

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.118A>C (p.S40R) alteration is located in exon 1 (coding exon 1) of the HSPA1A gene. This alteration results from a A to C substitution at nucleotide position 118, causing the serine (S) at amino acid position 40 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.36

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.96

MutPred

0.88

Gain of phosphorylation at T38 (P = 0.1192);

MVP

0.65

ClinPred

0.99

GERP RS

4.1

Varity_R

0.44

gMVP

0.99

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

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