NM_031407.7:c.13070G>A

Variant names:

• chrX-53533364-C-T
• rs2060850988
• NM_031407.7:c.13070G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The NM_031407.7(HUWE1):​c.13070G>A​(p.Arg4357His) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,015 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.00

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the HUWE1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 70 curated benign missense variants. Gene score misZ: 8.8732 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic intellectual disability, intellectual disability, X-linked syndromic, Turner type, non-syndromic X-linked intellectual disability.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.762
• PP5: Variant X-53533364-C-T is Pathogenic according to our data. Variant chrX-53533364-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 870389.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.13070G>A	p.Arg4357His	missense_variant	Exon 84 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.13070G>A	p.Arg4357His	missense_variant	Exon 84 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095015 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 360461

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

HUWE1-related neurodevelopmental disorder Pathogenic:1

Feb 17, 2018

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variant, NM_031407.5(HUWE1):c.13070G>A, has been identified in exon 84 of 84 of the HUWE1 gene. The variant is predicted to result in a minor amino acid change from arginine to histidine at position 4357 of the protein (NP_113584.3(HUWE1):p.(Arg4357His)). The arginine residue at this position has very high conservation (100 vertebrates, UCSC), and is located within the HECT functional domain. In-silico predictions for this variant are consistently pathogenic (Polyphen, CADD, Mutation Taster). The variant is absent in population databases (gnomAD). This variant has not been previously reported in clinical cases. Subsequent analysis of parental samples indicated this variant to be de novo. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -

Inborn genetic diseases Uncertain:1

Jul 30, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13070G>A (p.R4357H) alteration is located in exon 84 (coding exon 81) of the HUWE1 gene. This alteration results from a G to A substitution at nucleotide position 13070, causing the arginine (R) at amino acid position 4357 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	.;T;T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T;.;T
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	.;M;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	.;D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.028	.;D;D
Sift4G	Uncertain	0.056	T;T;T
Polyphen		1.0	.;D;D
Vest4		0.61
MutPred		0.66		.;Gain of catalytic residue at M4359 (P = 0.0612);Gain of catalytic residue at M4359 (P = 0.0612);
MVP		0.86
MPC		1.7
ClinPred		0.97	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.92

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: rs2060850988; hg19: chrX-53560325; COSMIC: COSV53346002; COSMIC: COSV53346002;