chr6-31817308-A-G

Variant names:

• chr6-31817308-A-G
• rs754012082
• NM_005345.6:c.1552A>G

Variant summary

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

The NM_005345.6(HSPA1A):​c.1552A>G​(p.Met518Val) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000029 (0 hom., cov: 17)
  • Exomes 𝑓: 0.0000086 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA1A	NM_005345.6	c.1552A>G	p.Met518Val	missense_variant	Exon 1 of 1	ENST00000375651.7	NP_005336.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA1A	ENST00000375651.7	c.1552A>G	p.Met518Val	missense_variant	Exon 1 of 1	6	NM_005345.6	ENSP00000364802.5
HSPA1A	ENST00000608703.2	c.1057A>G	p.Met353Val	missense_variant	Exon 2 of 2	2		ENSP00000477378.1

Frequencies

GnomAD3 genomes AF: 0.0000292 AC: 4 AN: 136778 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000560

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: 0.0000314

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000135 AC: 2 AN: 147736 AF XY: 0.00

Gnomad AFR exome AF: 0.000140

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: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000856 AC: 12 AN: 1401242 Hom.: 0 Cov.: 28 AF XY: 0.00000722 AC XY: 5 AN XY: 692784

African (AFR) AF: 0.0000626 AC: 2 AN: 31944

American (AMR) AF: 0.00 AC: 0 AN: 36824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25110

East Asian (EAS) AF: 0.00 AC: 0 AN: 36956

South Asian (SAS) AF: 0.00 AC: 0 AN: 81206

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4176

European-Non Finnish (NFE) AF: 0.00000742 AC: 8 AN: 1077780

Other (OTH) AF: 0.0000172 AC: 1 AN: 58074

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000292 AC: 4 AN: 136778 Hom.: 0 Cov.: 17 AF XY: 0.0000152 AC XY: 1 AN XY: 65740

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

African (AFR) AF: 0.0000560 AC: 2 AN: 35742

American (AMR) AF: 0.00 AC: 0 AN: 13354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3288

East Asian (EAS) AF: 0.00 AC: 0 AN: 4702

South Asian (SAS) AF: 0.00 AC: 0 AN: 3874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.0000314 AC: 2 AN: 63676

Other (OTH) AF: 0.00 AC: 0 AN: 1798

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000266), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000843 Hom.: 0

ExAC AF: 0.00000963 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1552A>G (p.M518V) alteration is located in exon 1 (coding exon 1) of the HSPA1A gene. This alteration results from a A to G substitution at nucleotide position 1552, causing the methionine (M) at amino acid position 518 to be replaced by a valine (V). 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	Benign	-0.14	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		9.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Vest4		0.62
MutPred		0.72		Loss of MoRF binding (P = 0.1376);.;
MVP		0.29
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.22
gMVP		0.51
Mutation Taster		=88/12	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: rs754012082; hg19: chr6-31785085;