rs1556948950

Positions:

• chrX-53569655-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_031407.7(HUWE1):​c.6485G>C​(p.Arg2162Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.6485G>C	p.Arg2162Pro	missense_variant	48/84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.6485G>C	p.Arg2162Pro	missense_variant	48/84	1	NM_031407.7	ENSP00000262854	P2
HUWE1	ENST00000342160.7	c.6485G>C	p.Arg2162Pro	missense_variant	47/83	5		ENSP00000340648	P2
HUWE1	ENST00000612484.4	c.6458G>C	p.Arg2153Pro	missense_variant	45/81	5		ENSP00000479451	A2
HUWE1	ENST00000704099.1	c.6482G>C	p.Arg2161Pro	missense_variant	47/83			ENSP00000515693

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Blepharophimosis;C0018817:Atrial septal defect;C0018818:Ventricular septal defect;C0020676:Hypothyroidism;C0424503:Abnormal facial shape;C1837397:Severe global developmental delay;C3665347:Visual impairment;C4024890:Excessive wrinkled skin Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;.;D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.1	.;M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.3	.;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.79
MutPred		0.63		.;Loss of methylation at R2162 (P = 0.0132);Loss of methylation at R2162 (P = 0.0132);
MVP		0.91
MPC		2.5
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.91

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: rs1556948950; hg19: chrX-53596615;