rs1556948950

Variant names:

• chrX-53569655-C-G
• rs1556948950
• NM_031407.7:c.6485G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2162W) has been classified 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
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

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.6485G>C	p.Arg2162Pro	missense	Exon 48 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.6485G>C	p.Arg2162Pro	missense	Exon 47 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.6482G>C	p.Arg2161Pro	missense	Exon 48 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.6485G>C	p.Arg2162Pro	missense	Exon 48 of 84	ENSP00000262854.6
	HUWE1	ENST00000342160.7	TSL:5	c.6485G>C	p.Arg2162Pro	missense	Exon 47 of 83	ENSP00000340648.3
	HUWE1	ENST00000612484.4	TSL:5	c.6458G>C	p.Arg2153Pro	missense	Exon 45 of 81	ENSP00000479451.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	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 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.087	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.63		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
Mutation Taster		=54/46	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: rs1556948950; hg19: chrX-53596615;