7-43311786-A-T

Variant names:

• chr7-43311786-A-T
• NM_015052.5:c.51A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015052.5(HECW1):​c.51A>T​(p.Leu17Phe) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HECW1 NM_015052.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26974574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECW1	NM_015052.5	c.51A>T	p.Leu17Phe	missense_variant	Exon 4 of 30	ENST00000395891.7	NP_055867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW1	ENST00000395891.7	c.51A>T	p.Leu17Phe	missense_variant	Exon 4 of 30	1	NM_015052.5	ENSP00000379228.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.51A>T (p.L17F) alteration is located in exon 4 (coding exon 2) of the HECW1 gene. This alteration results from a A to T substitution at nucleotide position 51, causing the leucine (L) at amino acid position 17 to be replaced by a phenylalanine (F). 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	0.48
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.059
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		0.47
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.72	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		0.99	D;.
Vest4		0.53
MutPred		0.25		Loss of MoRF binding (P = 0.1131);Loss of MoRF binding (P = 0.1131);
MVP		0.25
MPC		0.65
ClinPred		0.55	D
GERP RS		-1.2
Varity_R		0.10
gMVP		0.35
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

hg19: chr7-43351385;