dbSNP rs782009073: HUWE1:c.10035+6G>A (chrX-53548953-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_031407.7(HUWE1):c.10035+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000876 in 1,186,964 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 56 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000086 ( 0 hom. 50 hem. )

Consequence

HUWE1
NM_031407.7 splice_region, intron

Scores

Splicing: ADA: 0.0001336

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.565

Publications

1 publications found

Variant links:

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

HUWE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant X-53548953-C-T is Benign according to our data. Variant chrX-53548953-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 191249.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000107 (12/111917) while in subpopulation SAS AF = 0.00461 (12/2602). AF 95% confidence interval is 0.00266. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 12 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
HUWE1	NM_031407.7	MANE Select	c.10035+6G>A	splice_region intron	N/A	NP_113584.3
HUWE1	NM_001441057.1		c.10035+6G>A	splice_region intron	N/A	NP_001427986.1
HUWE1	NM_001441051.1		c.10032+6G>A	splice_region intron	N/A	NP_001427980.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HUWE1	ENST00000262854.11	TSL:1 MANE Select	c.10035+6G>A	splice_region intron	N/A	ENSP00000262854.6	Q7Z6Z7-1
HUWE1	ENST00000342160.7	TSL:5	c.10035+6G>A	splice_region intron	N/A	ENSP00000340648.3	Q7Z6Z7-1
HUWE1	ENST00000612484.4	TSL:5	c.10008+6G>A	splice_region intron	N/A	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes

AF:

0.000107

AC:

AN:

111865

Hom.:

Cov.:

show subpopulations

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:

0.00459

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000204

AC:

AN:

142033

AF XY:

0.000347

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000260

GnomAD4 exome

AF:

0.0000856

AC:

AN:

1075047

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

349553

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25817

American (AMR)

AF:

0.00

AC:

AN:

31610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18956

East Asian (EAS)

AF:

0.00

AC:

AN:

28963

South Asian (SAS)

AF:

0.00163

AC:

AN:

51492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3943

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

829701

Other (OTH)

AF:

0.000154

AC:

AN:

45325

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000107

AC:

AN:

111917

Hom.:

Cov.:

AF XY:

0.000176

AC XY:

AN XY:

34107

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30823

American (AMR)

AF:

0.00

AC:

AN:

10618

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3559

South Asian (SAS)

AF:

0.00461

AC:

AN:

2602

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53124

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.56

PhyloP100

0.56

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00013

dbscSNV1_RF

Benign

0.040

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over