X-53580885-C-T

Position:

• chrX-53580885-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_031407.7(HUWE1):​c.5662G>A​(p.Val1888Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,173 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.63

Genes affected

HUWE1 (HGNC:30892): (HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1) This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), HUWE1. . Gene score misZ 8.8732 (greater than the threshold 3.09). GenCC has associacion of gene with syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40481332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.5662G>A	p.Val1888Met	missense_variant	43/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.5662G>A	p.Val1888Met	missense_variant	43/84	1	NM_031407.7	ENSP00000262854	P2
HUWE1	ENST00000342160.7	c.5662G>A	p.Val1888Met	missense_variant	42/83	5		ENSP00000340648	P2
HUWE1	ENST00000612484.4	c.5635G>A	p.Val1879Met	missense_variant	40/81	5		ENSP00000479451	A2
HUWE1	ENST00000704099.1	c.5662G>A	p.Val1888Met	missense_variant	42/83			ENSP00000515693

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183233 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67695

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098173 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363527

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2017

- -

Intellectual disability, X-linked syndromic, Turner type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 22, 2019

The HUWE1 c.5662G>A (p.Val1888Met) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000036 in the Latino population of the Genome Aggregation Database but this is based on one allele in an area of good sequence coverage so the variant is presumed to be rare. Based on the limited evidence, the p.Val1888Met variant is classified as a variant of uncertain significance for X-linked syndromic intellectual disability, Turner type. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	.;L;L
MutationTaster	Benign	0.81	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	.;N;N
REVEL	Benign	0.25
Sift	Uncertain	0.015	.;D;D
Sift4G	Uncertain	0.050	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.41
MutPred		0.27		.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.71
MPC		1.4
ClinPred		0.64	D
GERP RS		5.8
Varity_R		0.24
gMVP		0.68

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: rs782222601; hg19: chrX-53607845;