chrX-53628620-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_031407.7(HUWE1):​c.1115A>T​(p.Asp372Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000376 in 1,064,501 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D372N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 4 hem.)
• Consequence: HUWE1 NM_031407.7 missense, splice_region
• Scores: Splicing: ADA: 0.1977
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
• 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 -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 4 XL,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	NM_031407.7	MANE Select	c.1115A>T	p.Asp372Val	missense splice_region	Exon 15 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.1115A>T	p.Asp372Val	missense splice_region	Exon 14 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.1115A>T	p.Asp372Val	missense splice_region	Exon 15 of 84	NP_001427980.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HUWE1	ENST00000262854.11	TSL:1 MANE Select	c.1115A>T	p.Asp372Val	missense splice_region	Exon 15 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.1115A>T	p.Asp372Val	missense splice_region	Exon 14 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.1115A>T	p.Asp372Val	missense splice_region	Exon 12 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000376 AC: 4 AN: 1064501 Hom.: 0 Cov.: 32 AF XY: 0.0000115 AC XY: 4 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: 0.00000485 AC: 4 AN: 824572

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

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.050	T
Polyphen		0.97	D
Vest4		0.74
MutPred		0.42		Gain of catalytic residue at D372 (P = 0.0223)
MVP		0.92
MPC		1.9
ClinPred		0.90	D
GERP RS		5.7
PromoterAI		-0.0044	Neutral
Varity_R		0.43
gMVP		0.84
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.20
dbscSNV1_RF	Benign	0.49
SpliceAI score (max)		0.010		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;