rs145758265

Variant names:

• chrX-53600199-T-C
• rs145758265
• NM_031407.7:c.3082A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_031407.7(HUWE1):​c.3082A>G​(p.Thr1028Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000751 in 1,207,806 control chromosomes in the GnomAD database, including 2 homozygotes. There are 309 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., 24 hem., cov: 23)
  • Exomes 𝑓: 0.00075 (2 hom. 285 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 2.44
• Publications: 5 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046494603).
• BP6: Variant X-53600199-T-C is Benign according to our data. Variant chrX-53600199-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196188.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00074 (83/112210) while in subpopulation NFE AF = 0.00117 (62/53171). AF 95% confidence interval is 0.000934. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 83 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.3082A>G	p.Thr1028Ala	missense	Exon 29 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.3082A>G	p.Thr1028Ala	missense	Exon 28 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.3082A>G	p.Thr1028Ala	missense	Exon 29 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.3082A>G	p.Thr1028Ala	missense	Exon 29 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.3082A>G	p.Thr1028Ala	missense	Exon 28 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.3055A>G	p.Thr1019Ala	missense	Exon 26 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.000740 AC: 83 AN: 112157 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00309

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.000662

GnomAD2 exomes AF: 0.000960 AC: 176 AN: 183253 AF XY: 0.000945

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00463

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000884

GnomAD4 exome AF: 0.000752 AC: 824 AN: 1095596 Hom.: 2 Cov.: 30 AF XY: 0.000789 AC XY: 285 AN XY: 360990

African (AFR) AF: 0.0000379 AC: 1 AN: 26358

American (AMR) AF: 0.0000568 AC: 2 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19363

East Asian (EAS) AF: 0.00 AC: 0 AN: 30193

South Asian (SAS) AF: 0.00 AC: 0 AN: 54066

European-Finnish (FIN) AF: 0.00540 AC: 219 AN: 40528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.000672 AC: 564 AN: 839754

Other (OTH) AF: 0.000826 AC: 38 AN: 46006

GnomAD4 genome AF: 0.000740 AC: 83 AN: 112210 Hom.: 0 Cov.: 23 AF XY: 0.000698 AC XY: 24 AN XY: 34364

African (AFR) AF: 0.0000324 AC: 1 AN: 30898

American (AMR) AF: 0.00 AC: 0 AN: 10679

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3556

South Asian (SAS) AF: 0.00 AC: 0 AN: 2692

European-Finnish (FIN) AF: 0.00309 AC: 19 AN: 6139

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00117 AC: 62 AN: 53171

Other (OTH) AF: 0.000654 AC: 1 AN: 1530

Alfa AF: 0.00105 Hom.: 48

Bravo AF: 0.000400

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00104 AC: 7

ExAC AF: 0.00134 AC: 163

EpiCase AF: 0.000600

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	1	HUWE1-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.052
Sift	Benign	0.73	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.075
MVP		0.44
MPC		0.92
ClinPred		0.0091	T
GERP RS		4.1
Varity_R		0.050
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs145758265; hg19: chrX-53627159; COSMIC: COSV106089600;