1-16015675-C-T

Position:

• chr1-16015675-C-T

Variant summary

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

The NM_014424.5(HSPB7):​c.418G>A​(p.Ala140Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPB7 NM_014424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

HSPB7 (HGNC:5249): (heat shock protein family B (small) member 7) This gene encodes a small heat shock family B member that can heterodimerize with similar heat shock proteins. Defects in this gene are associated with advanced heart failure. In addition, the encoded protein may be a tumor suppressor in the p53 pathway, with defects in this gene being associated with renal cell carcinoma. [provided by RefSeq, Mar 2017]

HSPB7 (HGNC:):

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=0.37495628).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPB7	NM_014424.5	c.418G>A	p.Ala140Thr	missense_variant	3/3	ENST00000311890.14	NP_055239.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPB7	ENST00000311890.14	c.418G>A	p.Ala140Thr	missense_variant	3/3	1	NM_014424.5	ENSP00000310111.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Aug 20, 2024

The c.418G>A (p.A140T) alteration is located in exon 3 (coding exon 3) of the HSPB7 gene. This alteration results from a G to A substitution at nucleotide position 418, causing the alanine (A) at amino acid position 140 to be replaced by a threonine (T). 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	0.087
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	.;T;.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.37	T;T;T;T;T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.91	.;L;.;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.22	N;N;N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.23	T;T;T;T;T;T
Sift4G	Uncertain	0.023	D;D;T;T;D;D
Polyphen		0.0020, 0.32	.;B;B;.;.;.
Vest4		0.094
MutPred		0.33		.;.;Gain of glycosylation at S214 (P = 0.0423);.;.;.;
MVP		0.94
MPC		0.35
ClinPred		0.28	T
GERP RS		5.0
Varity_R		0.065
gMVP		0.24

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

LitVar

Other links and lift over

dbSNP: rs2021659064; hg19: chr1-16342170;