rs782375893

Variant names:

• chrX-53550683-ACCC-A
• rs782375893
• NM_031407.7:c.9468_9470delGGG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_031407.7(HUWE1):​c.9468_9470delGGG​(p.Gly3157del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000174 in 1,208,160 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: HUWE1 NM_031407.7 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.15
• 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), Ambry Genetics, G2P, 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 -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_031407.7. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-53550683-ACCC-A is Benign according to our data. Variant chrX-53550683-ACCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211171.
• BS2: High AC in GnomAdExome4 at 18 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.9468_9470delGGG	p.Gly3157del	disruptive_inframe_deletion	Exon 66 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.9468_9470delGGG	p.Gly3157del	disruptive_inframe_deletion	Exon 65 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.9465_9467delGGG	p.Gly3156del	disruptive_inframe_deletion	Exon 66 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.9468_9470delGGG	p.Gly3157del	disruptive_inframe_deletion	Exon 66 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.9468_9470delGGG	p.Gly3157del	disruptive_inframe_deletion	Exon 65 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.9441_9443delGGG	p.Gly3148del	disruptive_inframe_deletion	Exon 63 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110895 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000959

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183091 AF XY: 0.0000148

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: 0.0000612

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000164 AC: 18 AN: 1097265 Hom.: 0 AF XY: 0.0000165 AC XY: 6 AN XY: 362653

African (AFR) AF: 0.00 AC: 0 AN: 26386

American (AMR) AF: 0.0000284 AC: 1 AN: 35202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.0000178 AC: 15 AN: 841320

Other (OTH) AF: 0.0000434 AC: 2 AN: 46043

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110895 Hom.: 0 Cov.: 22 AF XY: 0.0000603 AC XY: 2 AN XY: 33161

African (AFR) AF: 0.00 AC: 0 AN: 30433

American (AMR) AF: 0.0000959 AC: 1 AN: 10426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5923

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52905

Other (OTH) AF: 0.00 AC: 0 AN: 1483

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000907

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.2
Mutation Taster		=84/16	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782375893;

hg19: chrX-53577644;