chrX-53580885-C-T

Variant names:

• chrX-53580885-C-T
• rs782222601
• NM_031407.7:c.5662G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1888L) has been classified 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:3
• Conservation: PhyloP100: 5.63
• Publications: 0 publications found

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]

HUWE1 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked syndromic, Turner type

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

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=0.40481332).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031407.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	NM_031407.7	MANE Select	c.5662G>A	p.Val1888Met	missense	Exon 43 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.5662G>A	p.Val1888Met	missense	Exon 42 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.5662G>A	p.Val1888Met	missense	Exon 43 of 84	NP_001427980.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	ENST00000262854.11	TSL:1 MANE Select	c.5662G>A	p.Val1888Met	missense	Exon 43 of 84	ENSP00000262854.6
	HUWE1	ENST00000342160.7	TSL:5	c.5662G>A	p.Val1888Met	missense	Exon 42 of 83	ENSP00000340648.3
	HUWE1	ENST00000612484.4	TSL:5	c.5635G>A	p.Val1879Met	missense	Exon 40 of 81	ENSP00000479451.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183233 AF XY: 0.00

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.0000284 AC: 1 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40529

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842090

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 18, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

May 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1888 of the HUWE1 protein (p.Val1888Met). This variant is present in population databases (rs782222601, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with HUWE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 521754). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HUWE1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Aug 22, 2019

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.25
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.050	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.27		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
Mutation Taster		=92/8	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

dbSNP: rs782222601; hg19: chrX-53607845;