NM_031407.7:c.10035+6G>T

Variant names:

• chrX-53548953-C-A
• rs782009073
• NM_031407.7:c.10035+6G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031407.7(HUWE1):​c.10035+6G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,075,047 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: HUWE1 NM_031407.7 splice_region, intron
• Scores: Splicing: ADA: 0.0001073
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.565
• 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: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, G2P
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.10035+6G>T		splice_region_variant, intron_variant	Intron 67 of 83	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.10035+6G>T		splice_region_variant, intron_variant	Intron 67 of 83	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075047 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 349553

African (AFR) AF: 0.00 AC: 0 AN: 25817

American (AMR) AF: 0.00 AC: 0 AN: 31609

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18956

East Asian (EAS) AF: 0.00 AC: 0 AN: 28963

South Asian (SAS) AF: 0.00 AC: 0 AN: 51492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3943

European-Non Finnish (NFE) AF: 0.00000121 AC: 1 AN: 829702

Other (OTH) AF: 0.00 AC: 0 AN: 45325

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	11
DANN	Benign	0.66
PhyloP100		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.038
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: rs782009073; hg19: chrX-53575914;