chr11-123059751-C-T

Variant names:

• chr11-123059751-C-T
• NM_006597.6:c.842G>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006597.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA8	NM_006597.6	MANE Select	c.842G>A	p.Ser281Asn	missense	Exon 5 of 9	NP_006588.1	P11142-1
	HSPA8	NM_153201.4		c.842G>A	p.Ser281Asn	missense	Exon 5 of 8	NP_694881.1	P11142-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA8	ENST00000534624.6	TSL:1 MANE Select	c.842G>A	p.Ser281Asn	missense	Exon 5 of 9	ENSP00000432083.1	P11142-1
	HSPA8	ENST00000227378.7	TSL:1	c.842G>A	p.Ser281Asn	missense	Exon 4 of 8	ENSP00000227378.3	P11142-1
	HSPA8	ENST00000453788.6	TSL:1	c.842G>A	p.Ser281Asn	missense	Exon 5 of 8	ENSP00000404372.2	P11142-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.64	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.21
Sift	Benign	0.061	T
Sift4G	Benign	0.23	T
Polyphen		0.0020	B
Vest4		0.61
MutPred		0.31		Loss of phosphorylation at S281 (P = 0.02)
MVP		0.19
ClinPred		0.90	D
GERP RS		4.8
PromoterAI		0.0024	Neutral
Varity_R		0.71
gMVP		0.45
Mutation Taster		=41/59	disease causing

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

Other links and lift over

hg19: chr11-122930459;