rs41307640

chrX-53627451-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031407.7(HUWE1):c.1448A>G(p.Asn483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,197,201 control chromosomes in the GnomAD database, including 320 homozygotes. There are 8,633 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (26 hom., 565 hem., cov: 22)
  • Exomes 𝑓: 0.024 (294 hom. 8068 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.03

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HUWE1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0015617311).
• BP6: Variant X-53627451-T-C is Benign according to our data. Variant chrX-53627451-T-C is described in ClinVar as [Benign]. Clinvar id is 129252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53627451-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0187 (2067/110542) while in subpopulation NFE AF= 0.0266 (1405/52872). AF 95% confidence interval is 0.0254. There are 26 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HUWE1	NM_031407.7	c.1448A>G	p.Asn483Ser	missense_variant	17/84	ENST00000262854.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HUWE1	ENST00000262854.11	c.1448A>G	p.Asn483Ser	missense_variant	17/84	1	NM_031407.7	P2

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2068 AN: 110497 Hom.: 26 Cov.: 22 AF XY: 0.0173 AC XY: 566 AN XY: 32719

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000757

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0305

GnomAD3 exomes AF: 0.0177 AC: 3236 AN: 182765 Hom.: 36 AF XY: 0.0171 AC XY: 1151 AN XY: 67239

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0765

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000637

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0241 AC: 26137 AN: 1086659 Hom.: 294 Cov.: 26 AF XY: 0.0228 AC XY: 8068 AN XY: 353459

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0746

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000781

Gnomad4 FIN exome AF: 0.0125

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0187 AC: 2067 AN: 110542 Hom.: 26 Cov.: 22 AF XY: 0.0172 AC XY: 565 AN XY: 32774

Gnomad4 AFR AF: 0.00305

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0779

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000380

Gnomad4 FIN AF: 0.0129

Gnomad4 NFE AF: 0.0266

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0259 Hom.: 1077

Bravo AF: 0.0189

ESP6500AA AF: 0.00391 AC: 15

ESP6500EA AF: 0.0275 AC: 185

ExAC AF: 0.0167 AC: 2023

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 08, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 13, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	1.2
Dann	Benign	0.24
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T;.;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.52	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.39	T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	.;B;B
Vest4		0.037
MPC		0.75
ClinPred		0.0028	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.23

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: rs41307640; hg19: chrX-53654402;