chrX-53628866-T-C

Variant names:

• chrX-53628866-T-C
• rs781928056
• NM_031407.7:c.1000A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_031407.7(HUWE1):​c.1000A>G​(p.Ile334Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000064 in 1,094,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I334T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.76
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25045785).
• BP6: Variant X-53628866-T-C is Benign according to our data. Variant chrX-53628866-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211157.
• BS2: High AC in GnomAdExome4 at 7 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.1000A>G	p.Ile334Val	missense_variant	Exon 14 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.1000A>G	p.Ile334Val	missense_variant	Exon 14 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000219 AC: 4 AN: 182541 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

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: 0.000221

GnomAD4 exome AF: 0.00000640 AC: 7 AN: 1094540 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 2 AN XY: 359962

African (AFR) AF: 0.00 AC: 0 AN: 26323

American (AMR) AF: 0.0000853 AC: 3 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 53992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000358 AC: 3 AN: 838853

Other (OTH) AF: 0.0000217 AC: 1 AN: 45994

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Apr 14, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I334V variant in the HUWE1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The I334V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, the I334V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret I334V as a variant of uncertain significance. -

not specified Benign:1

Dec 04, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;.;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.1	L;L;L
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.53	.;N;N
REVEL	Benign	0.21
Sift	Benign	0.25	.;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.66	.;P;P
Vest4		0.45
MutPred		0.70		Loss of catalytic residue at I334 (P = 0.0612);Loss of catalytic residue at I334 (P = 0.0612);Loss of catalytic residue at I334 (P = 0.0612);
MVP		0.79
MPC		1.2
ClinPred		0.39	T
GERP RS		4.5
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.14
gMVP		0.47
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs781928056; hg19: chrX-53655817;