chrX-53557457-G-A

Variant names:

• chrX-53557457-G-A
• rs17276588
• NM_031407.7:c.8161-30C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031407.7(HUWE1):​c.8161-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0441 in 1,149,755 control chromosomes in the GnomAD database, including 3,121 homozygotes. There are 15,489 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (321 hom., 1625 hem., cov: 22)
  • Exomes 𝑓: 0.044 (2800 hom. 13864 hem.)
• Consequence: HUWE1 NM_031407.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.761
• Publications: 21 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]

MIRLET7F2 (HGNC:31484): (microRNA let-7f-2) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-53557457-G-A is Benign according to our data. Variant chrX-53557457-G-A is described in ClinVar as Benign. ClinVar VariationId is 1226397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUWE1	NM_031407.7	c.8161-30C>T		intron_variant	Intron 59 of 83	ENST00000262854.11	NP_113584.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUWE1	ENST00000262854.11	c.8161-30C>T		intron_variant	Intron 59 of 83	1	NM_031407.7	ENSP00000262854.6

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 5122 AN: 111891 Hom.: 320 Cov.: 22

Gnomad AFR AF: 0.0112

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.295

Gnomad SAS AF: 0.0275

Gnomad FIN AF: 0.0356

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0231

Gnomad OTH AF: 0.0584

GnomAD2 exomes AF: 0.0900 AC: 16329 AN: 181518 AF XY: 0.0736

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.308

Gnomad ASJ exome AF: 0.0242

Gnomad EAS exome AF: 0.307

Gnomad FIN exome AF: 0.0394

Gnomad NFE exome AF: 0.0244

Gnomad OTH exome AF: 0.0610

GnomAD4 exome AF: 0.0439 AC: 45588 AN: 1037811 Hom.: 2800 Cov.: 25 AF XY: 0.0446 AC XY: 13864 AN XY: 310725

African (AFR) AF: 0.00691 AC: 175 AN: 25326

American (AMR) AF: 0.297 AC: 10426 AN: 35113

Ashkenazi Jewish (ASJ) AF: 0.0232 AC: 442 AN: 19038

East Asian (EAS) AF: 0.347 AC: 10412 AN: 29970

South Asian (SAS) AF: 0.0290 AC: 1534 AN: 52827

European-Finnish (FIN) AF: 0.0364 AC: 1438 AN: 39557

Middle Eastern (MID) AF: 0.00956 AC: 38 AN: 3975

European-Non Finnish (NFE) AF: 0.0242 AC: 19103 AN: 787837

Other (OTH) AF: 0.0457 AC: 2020 AN: 44168

GnomAD4 genome AF: 0.0458 AC: 5122 AN: 111944 Hom.: 321 Cov.: 22 AF XY: 0.0476 AC XY: 1625 AN XY: 34144

African (AFR) AF: 0.0112 AC: 345 AN: 30882

American (AMR) AF: 0.196 AC: 2070 AN: 10544

Ashkenazi Jewish (ASJ) AF: 0.0253 AC: 67 AN: 2646

East Asian (EAS) AF: 0.294 AC: 1031 AN: 3503

South Asian (SAS) AF: 0.0261 AC: 70 AN: 2687

European-Finnish (FIN) AF: 0.0356 AC: 217 AN: 6096

Middle Eastern (MID) AF: 0.0139 AC: 3 AN: 216

European-Non Finnish (NFE) AF: 0.0231 AC: 1229 AN: 53157

Other (OTH) AF: 0.0583 AC: 89 AN: 1526

Alfa AF: 0.0209 Hom.: 224

Bravo AF: 0.0612

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.44
DANN	Benign	0.25
PhyloP100		-0.76
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17276588; hg19: chrX-53584418;