7-43396863-G-C

Variant names:

• chr7-43396863-G-C
• rs779347290
• NM_015052.5:c.605G>C

Variant summary

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

The NM_015052.5(HECW1):​c.605G>C​(p.Arg202Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HECW1 NM_015052.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80
• Publications: 5 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.605G>C	p.Arg202Pro	missense_variant	Exon 7 of 30	ENST00000395891.7	NP_055867.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECW1	ENST00000395891.7	c.605G>C	p.Arg202Pro	missense_variant	Exon 7 of 30	1	NM_015052.5	ENSP00000379228.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460602 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726678

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86206

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5220

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111588

Other (OTH) AF: 0.00 AC: 0 AN: 60304

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000660 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.67	D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		5.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.58		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MVP		0.37
MPC		1.6
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.78
gMVP		0.83
Mutation Taster		=38/62	disease causing

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

dbSNP: rs779347290; hg19: chr7-43436462; COSMIC: COSV101223022;