X-53580885-C-G

Position:

• chrX-53580885-C-G

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>C​(p.Val1888Leu) variant causes a missense change. 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: 23)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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=0.37009233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.5662G>C	p.Val1888Leu	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>C	p.Val1888Leu	missense_variant	43/84	1	NM_031407.7	ENSP00000262854	P2
HUWE1	ENST00000342160.7	c.5662G>C	p.Val1888Leu	missense_variant	42/83	5		ENSP00000340648	P2
HUWE1	ENST00000612484.4	c.5635G>C	p.Val1879Leu	missense_variant	40/81	5		ENSP00000479451	A2
HUWE1	ENST00000704099.1	c.5662G>C	p.Val1888Leu	missense_variant	42/83			ENSP00000515693

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 02, 2022

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.36	.;T;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.90	.;L;L
MutationTaster	Benign	0.79	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.9	.;N;N
REVEL	Benign	0.10
Sift	Benign	0.051	.;T;T
Sift4G	Benign	0.17	T;T;T
Polyphen		0.82	.;P;P
Vest4		0.41
MutPred		0.25		.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP		0.64
MPC		1.4
ClinPred		0.73	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.73

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;