7-43438015-G-A

Variant names:

• chr7-43438015-G-A
• NM_015052.5:c.814G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015052.5(HECW1):​c.814G>A​(p.Val272Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HECW1 NM_015052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.04
• Publications: 0 publications found

Genes affected

HECW1 (HGNC:22195): (HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in several processes, including cellular protein metabolic process; negative regulation of sodium ion transmembrane transporter activity; and regulation of dendrite morphogenesis. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW1	NM_015052.5	c.814G>A	p.Val272Met	missense_variant	Exon 9 of 30	ENST00000395891.7	NP_055867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW1	ENST00000395891.7	c.814G>A	p.Val272Met	missense_variant	Exon 9 of 30	1	NM_015052.5	ENSP00000379228.1
HECW1	ENST00000453890.5	c.814G>A	p.Val272Met	missense_variant	Exon 8 of 28	2		ENSP00000407774.1
HECW1	ENST00000471043.1	n.306G>A		non_coding_transcript_exon_variant	Exon 4 of 4	2
HECW1	ENST00000492310.5	n.1438G>A		non_coding_transcript_exon_variant	Exon 7 of 7	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.814G>A (p.V272M) alteration is located in exon 9 (coding exon 7) of the HECW1 gene. This alteration results from a G to A substitution at nucleotide position 814, causing the valine (V) at amino acid position 272 to be replaced by a methionine (M). 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	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;M
PhyloP100		8.0
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.017	D;D
Polyphen		1.0	D;.
Vest4		0.54
MutPred		0.51		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);
MVP		0.62
MPC		1.4
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.41
gMVP		0.45
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr7-43477614;