X-53628620-T-C

Variant names:

• chrX-53628620-T-C
• rs797045617
• NM_031407.7:c.1115A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_031407.7(HUWE1):​c.1115A>G​(p.Asp372Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,064,501 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D372Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000056 (0 hom. 1 hem.)
• Consequence: HUWE1 NM_031407.7 missense, splice_region
• Scores: Splicing: ADA: 0.03838
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.77
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3789918).
• BS2: High AC in GnomAdExome4 at 6 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.1115A>G	p.Asp372Gly	missense_variant, splice_region_variant	Exon 15 of 84	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.1115A>G	p.Asp372Gly	missense_variant, splice_region_variant	Exon 15 of 84	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000564 AC: 6 AN: 1064501 Hom.: 0 Cov.: 32 AF XY: 0.00000288 AC XY: 1 AN XY: 347259

African (AFR) AF: 0.00 AC: 0 AN: 25166

American (AMR) AF: 0.00 AC: 0 AN: 29821

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18895

East Asian (EAS) AF: 0.00 AC: 0 AN: 27686

South Asian (SAS) AF: 0.00 AC: 0 AN: 50655

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38732

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4106

European-Non Finnish (NFE) AF: 0.00000728 AC: 6 AN: 824572

Other (OTH) AF: 0.00 AC: 0 AN: 44868

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;.;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.49	N;N;N
PhyloP100		7.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.6	.;N;N
REVEL	Benign	0.21
Sift	Benign	0.30	.;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.073	.;B;B
Vest4		0.59
MutPred		0.38		Gain of catalytic residue at D372 (P = 0.017);Gain of catalytic residue at D372 (P = 0.017);Gain of catalytic residue at D372 (P = 0.017);
MVP		0.93
MPC		1.2
ClinPred		0.59	D
GERP RS		5.7
PromoterAI		0.00080	Neutral
Varity_R		0.33
gMVP		0.79
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.038
dbscSNV1_RF	Benign	0.32
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: rs797045617; hg19: chrX-53655571;