rs201226547

Variant names:

• chrX-53585071-T-A
• rs201226547
• NM_031407.7:c.4942A>T
• HUWE1 p.Ser1648Cys

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_031407.7(HUWE1):​c.4942A>T​(p.Ser1648Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000364 in 1,098,204 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1648S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.69
• 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: 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 (MetaRNN=0.3284924).
• BP6: Variant X-53585071-T-A is Benign according to our data. Variant chrX-53585071-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 375715.

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.4942A>T	p.Ser1648Cys	missense	Exon 40 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.4942A>T	p.Ser1648Cys	missense	Exon 39 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.4942A>T	p.Ser1648Cys	missense	Exon 40 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.4942A>T	p.Ser1648Cys	missense	Exon 40 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.4942A>T	p.Ser1648Cys	missense	Exon 39 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.4915A>T	p.Ser1639Cys	missense	Exon 37 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1098204 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363558

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4130

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 842097

Other (OTH) AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, X-linked syndromic, Turner type (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.26
Sift	Benign	0.065	T
Sift4G	Benign	0.11	T
Varity_R		0.39
gMVP		0.95
Mutation Taster		=69/31	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: rs201226547;

hg19: chrX-53612031;