rs140734968

Variant names:

• chrX-53535460-G-C
• rs140734968
• NM_031407.7:c.12573C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-53535460-G-C
• chrX-53535460-G-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_031407.7(HUWE1):​c.12573C>G​(p.Pro4191Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00177 in 1,206,433 control chromosomes in the GnomAD database, including 21 homozygotes. There are 691 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 128 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (20 hom. 563 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.977
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.015).
• BP6: Variant X-53535460-G-C is Benign according to our data. Variant chrX-53535460-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129244.
• BP7: Synonymous conserved (PhyloP=0.977 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00229 (255/111163) while in subpopulation NFE AF = 0.00083 (44/53025). AF 95% confidence interval is 0.000634. There are 1 homozygotes in GnomAd4. There are 128 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 255 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.12573C>G	p.Pro4191Pro	synonymous	Exon 81 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.12573C>G	p.Pro4191Pro	synonymous	Exon 80 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.12570C>G	p.Pro4190Pro	synonymous	Exon 81 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.12573C>G	p.Pro4191Pro	synonymous	Exon 81 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.12573C>G	p.Pro4191Pro	synonymous	Exon 80 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.12546C>G	p.Pro4182Pro	synonymous	Exon 78 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 255 AN: 111111 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000164

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: 0.0345

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000830

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.00322 AC: 590 AN: 183250 AF XY: 0.00281

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0297

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.00243

GnomAD4 exome AF: 0.00172 AC: 1882 AN: 1095270 Hom.: 20 Cov.: 29 AF XY: 0.00156 AC XY: 563 AN XY: 360722

African (AFR) AF: 0.00 AC: 0 AN: 26354

American (AMR) AF: 0.000170 AC: 6 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30191

South Asian (SAS) AF: 0.00 AC: 0 AN: 54083

European-Finnish (FIN) AF: 0.0306 AC: 1235 AN: 40386

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4133

European-Non Finnish (NFE) AF: 0.000688 AC: 578 AN: 839574

Other (OTH) AF: 0.00133 AC: 61 AN: 45983

GnomAD4 genome AF: 0.00229 AC: 255 AN: 111163 Hom.: 1 Cov.: 23 AF XY: 0.00383 AC XY: 128 AN XY: 33445

African (AFR) AF: 0.000163 AC: 5 AN: 30588

American (AMR) AF: 0.00 AC: 0 AN: 10390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2602

European-Finnish (FIN) AF: 0.0345 AC: 205 AN: 5935

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000830 AC: 44 AN: 53025

Other (OTH) AF: 0.000657 AC: 1 AN: 1522

Alfa AF: 0.00124 Hom.: 9

EpiCase AF: 0.000382

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	1	HUWE1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.3
DANN	Benign	0.59
PhyloP100		0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140734968; hg19: chrX-53562421;