Variant 1-161524971-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002155.5(HSPA6):c.313G>T(p.Val105Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,613,446 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

HSPA6
NM_002155.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.92

Variant links:

Genes affected

HSPA6 (HGNC:5239): (heat shock protein family A (Hsp70) member 6) Enables enzyme binding activity; heat shock protein binding activity; and unfolded protein binding activity. Involved in cellular response to heat and protein refolding. Located in centriole and cytosol. Colocalizes with COP9 signalosome. [provided by Alliance of Genome Resources, Apr 2022]

HSPA6 links:

ENSG00000273112 (HGNC:):

ENSG00000273112 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10291597).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA6	NM_002155.5 linkuse as main transcript	c.313G>T	p.Val105Leu	missense_variant	1/1	ENST00000309758.6	NP_002146.2	P17066A0A384NKX5B3KSM6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA6	ENST00000309758.6 linkuse as main transcript	c.313G>T	p.Val105Leu	missense_variant	1/1	6	NM_002155.5	ENSP00000310219.4		P17066
ENSG00000273112	ENST00000537821.2 linkuse as main transcript	n.271+6834G>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000100

AC:

AN:

249896

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135522

show subpopulations

Gnomad AFR exome

AF:

0.000189

Gnomad AMR exome

AF:

0.00

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:

0.000186

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461342

Hom.:

Cov.:

AF XY:

0.000193

AC XY:

140

AN XY:

726990

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000447

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:

0.000242

Gnomad4 OTH exome

AF:

0.000282

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000742

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000119

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

Feb 14, 2023

The c.313G>T (p.V105L) alteration is located in exon 1 (coding exon 1) of the HSPA6 gene. This alteration results from a G to T substitution at nucleotide position 313, causing the valine (V) at amino acid position 105 to be replaced by a leucine (L). 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

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.0029

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.48

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.0023

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.85

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.63

REVEL

Benign

0.029

Sift

Uncertain

0.026

Sift4G

Benign

0.11

Polyphen

0.015

Vest4

0.28

MutPred

0.35

Loss of methylation at K104 (P = 0.0452);

MVP

0.13

ClinPred

0.039

GERP RS

2.7

Varity_R

0.29

gMVP

0.15

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