X-53534144-C-T

Variant names:

• chrX-53534144-C-T
• rs1325394060
• NM_031407.7:c.12885G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_031407.7(HUWE1):​c.12885G>A​(p.Lys4295Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000009 in 111,158 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
• Consequence: HUWE1 NM_031407.7 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70
• Publications: 3 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.012).
• BP7: Synonymous conserved (PhyloP=2.7 with no splicing effect.

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.12885G>A	p.Lys4295Lys	synonymous	Exon 83 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.12885G>A	p.Lys4295Lys	synonymous	Exon 82 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.12882G>A	p.Lys4294Lys	synonymous	Exon 83 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.12885G>A	p.Lys4295Lys	synonymous	Exon 83 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.12885G>A	p.Lys4295Lys	synonymous	Exon 82 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.12858G>A	p.Lys4286Lys	synonymous	Exon 80 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.00000900 AC: 1 AN: 111158 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000900 AC: 1 AN: 111158 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33320

African (AFR) AF: 0.00 AC: 0 AN: 30543

American (AMR) AF: 0.00 AC: 0 AN: 10407

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3539

South Asian (SAS) AF: 0.00 AC: 0 AN: 2593

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53042

Other (OTH) AF: 0.00 AC: 0 AN: 1491

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.58
PhyloP100		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1325394060; hg19: chrX-53561105; COSMIC: COSV99471111; COSMIC: COSV99471111;