14-64542257-G-T

Position:

• chr14-64542257-G-T

Variant summary

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

The NM_021979.4(HSPA2):​c.1408G>T​(p.Ala470Ser) variant causes a missense change. 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: 31)
• Consequence: HSPA2 NM_021979.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

HSPA2 (HGNC:5235): (heat shock protein family A (Hsp70) member 2) Enables disordered domain specific binding activity; enzyme binding activity; and unfolded protein binding activity. Involved in negative regulation of inclusion body assembly and protein refolding. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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=0.3541644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA2	NM_021979.4	c.1408G>T	p.Ala470Ser	missense_variant	1/1	ENST00000247207.7	NP_068814.2
HSPA2	NM_001387931.1	c.1408G>T	p.Ala470Ser	missense_variant	2/2		NP_001374860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA2	ENST00000247207.7	c.1408G>T	p.Ala470Ser	missense_variant	1/1		NM_021979.4	ENSP00000247207	P1
HSPA2	ENST00000394709.2	c.1408G>T	p.Ala470Ser	missense_variant	2/2	1		ENSP00000378199	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 86

GnomAD4 genome Cov.: 31

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

Feb 28, 2023

The c.1408G>T (p.A470S) alteration is located in exon 1 (coding exon 1) of the HSPA2 gene. This alteration results from a G to T substitution at nucleotide position 1408, causing the alanine (A) at amino acid position 470 to be replaced by a serine (S). 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	0.30
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.39	B;B
Vest4		0.32
MutPred		0.65		Gain of catalytic residue at P469 (P = 0);Gain of catalytic residue at P469 (P = 0);
MVP		0.41
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.33
gMVP		0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-65008975;