rs1556978515

Variant names:

• chrX-53591113-T-C
• rs1556978515
• NM_031407.7:c.3982A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_031407.7(HUWE1):​c.3982A>G​(p.Met1328Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57
• Publications: 1 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53591113-T-C is Pathogenic according to our data. Variant chrX-53591113-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 375714.Status of the report is criteria_provided_single_submitter, 1 stars.

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.3982A>G	p.Met1328Val	missense	Exon 34 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.3982A>G	p.Met1328Val	missense	Exon 33 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.3982A>G	p.Met1328Val	missense	Exon 34 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.3982A>G	p.Met1328Val	missense	Exon 34 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.3982A>G	p.Met1328Val	missense	Exon 33 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.3955A>G	p.Met1319Val	missense	Exon 31 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, X-linked syndromic, Turner type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	-0.0012	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.96	D
Vest4		0.47
MutPred		0.77		Loss of helix (P = 0.0558)
MVP		0.93
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.94
Mutation Taster		=11/89	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1556978515; hg19: chrX-53618073;