11-123059751-C-T

Position:

• chr11-123059751-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006597.6(HSPA8):​c.842G>A​(p.Ser281Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPA8 NM_006597.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

Genes affected

HSPA8 (HGNC:5241): (heat shock protein family A (Hsp70) member 8) This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3316453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA8	NM_006597.6	c.842G>A	p.Ser281Asn	missense_variant	5/9	ENST00000534624.6	NP_006588.1
HSPA8	NM_153201.4	c.842G>A	p.Ser281Asn	missense_variant	5/8		NP_694881.1
HSPA8	XM_011542798.2	c.842G>A	p.Ser281Asn	missense_variant	5/9		XP_011541100.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA8	ENST00000534624.6	c.842G>A	p.Ser281Asn	missense_variant	5/9	1	NM_006597.6	ENSP00000432083	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The c.842G>A (p.S281N) alteration is located in exon 5 (coding exon 4) of the HSPA8 gene. This alteration results from a G to A substitution at nucleotide position 842, causing the serine (S) at amino acid position 281 to be replaced by an asparagine (N). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;T;.;T;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;D;.;D;D;D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.64	N;.;N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.82	N;N;N;N;N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.061	T;T;T;.;T;T;T;D
Sift4G	Benign	0.23	T;T;T;T;T;T;T;.
Polyphen		0.0020	B;.;B;P;B;.;.;.
Vest4		0.61
MutPred		0.31		Loss of phosphorylation at S281 (P = 0.02);.;Loss of phosphorylation at S281 (P = 0.02);Loss of phosphorylation at S281 (P = 0.02);Loss of phosphorylation at S281 (P = 0.02);.;.;.;
MVP		0.19
ClinPred		0.90	D
GERP RS		4.8
Varity_R		0.71
gMVP		0.45

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-122930459;