rs149893977

Variant names:

• chrX-53584256-T-C
• rs149893977
• NM_031407.7:c.5091A>G

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.5091A>G​(p.Gly1697Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,203,279 control chromosomes in the GnomAD database, including 6 homozygotes. There are 930 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 0.0015 (0 hom., 52 hem., cov: 22)
  • Exomes 𝑓: 0.0023 (6 hom. 878 hem.)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.47
• 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=0.012).
• BP6: Variant X-53584256-T-C is Benign according to our data. Variant chrX-53584256-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211166.
• BP7: Synonymous conserved (PhyloP=-1.47 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00151 (169/111861) while in subpopulation SAS AF = 0.00532 (14/2631). AF 95% confidence interval is 0.00322. There are 0 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 169 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.5091A>G	p.Gly1697Gly	synonymous	Exon 41 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.5091A>G	p.Gly1697Gly	synonymous	Exon 40 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.5091A>G	p.Gly1697Gly	synonymous	Exon 41 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.5091A>G	p.Gly1697Gly	synonymous	Exon 41 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.5091A>G	p.Gly1697Gly	synonymous	Exon 40 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.5064A>G	p.Gly1688Gly	synonymous	Exon 38 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 168 AN: 111807 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000978

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000378

Gnomad ASJ AF: 0.00984

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00493

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.0126

Gnomad NFE AF: 0.00205

Gnomad OTH AF: 0.00398

GnomAD2 exomes AF: 0.00225 AC: 412 AN: 183375 AF XY: 0.00254

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.0107

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000440

Gnomad NFE exome AF: 0.00266

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00228 AC: 2491 AN: 1091418 Hom.: 6 Cov.: 29 AF XY: 0.00246 AC XY: 878 AN XY: 356904

African (AFR) AF: 0.000190 AC: 5 AN: 26277

American (AMR) AF: 0.000369 AC: 13 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 196 AN: 19348

East Asian (EAS) AF: 0.00 AC: 0 AN: 30187

South Asian (SAS) AF: 0.00519 AC: 280 AN: 53977

European-Finnish (FIN) AF: 0.000593 AC: 24 AN: 40462

Middle Eastern (MID) AF: 0.0102 AC: 42 AN: 4120

European-Non Finnish (NFE) AF: 0.00215 AC: 1800 AN: 835967

Other (OTH) AF: 0.00286 AC: 131 AN: 45878

GnomAD4 genome AF: 0.00151 AC: 169 AN: 111861 Hom.: 0 Cov.: 22 AF XY: 0.00153 AC XY: 52 AN XY: 34033

African (AFR) AF: 0.0000976 AC: 3 AN: 30747

American (AMR) AF: 0.000378 AC: 4 AN: 10589

Ashkenazi Jewish (ASJ) AF: 0.00984 AC: 26 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00532 AC: 14 AN: 2631

European-Finnish (FIN) AF: 0.000660 AC: 4 AN: 6062

Middle Eastern (MID) AF: 0.0138 AC: 3 AN: 218

European-Non Finnish (NFE) AF: 0.00205 AC: 109 AN: 53182

Other (OTH) AF: 0.00393 AC: 6 AN: 1528

Alfa AF: 0.00298 Hom.: 21

Bravo AF: 0.00153

EpiCase AF: 0.00447

EpiControl AF: 0.00267

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.5
DANN	Benign	0.71
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs149893977; hg19: chrX-53611216;