rs41307640

Variant names:

• chrX-53627451-T-C
• rs41307640
• NM_031407.7:c.1448A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031407.7(HUWE1):​c.1448A>G​(p.Asn483Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,197,201 control chromosomes in the GnomAD database, including 320 homozygotes. There are 8,633 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (26 hom., 565 hem., cov: 22)
  • Exomes 𝑓: 0.024 (294 hom. 8068 hem.)
• Consequence: HUWE1 NM_031407.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.03
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015617311).
• BP6: Variant X-53627451-T-C is Benign according to our data. Variant chrX-53627451-T-C is described in ClinVar as Benign. ClinVar VariationId is 129252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0187 (2067/110542) while in subpopulation NFE AF = 0.0266 (1405/52872). AF 95% confidence interval is 0.0254. There are 26 homozygotes in GnomAd4. There are 565 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2067 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.1448A>G	p.Asn483Ser	missense	Exon 17 of 84	NP_113584.3
	HUWE1	NM_001441057.1		c.1448A>G	p.Asn483Ser	missense	Exon 16 of 83	NP_001427986.1
	HUWE1	NM_001441051.1		c.1448A>G	p.Asn483Ser	missense	Exon 17 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.1448A>G	p.Asn483Ser	missense	Exon 17 of 84	ENSP00000262854.6	Q7Z6Z7-1
	HUWE1	ENST00000342160.7	TSL:5	c.1448A>G	p.Asn483Ser	missense	Exon 16 of 83	ENSP00000340648.3	Q7Z6Z7-1
	HUWE1	ENST00000612484.4	TSL:5	c.1448A>G	p.Asn483Ser	missense	Exon 14 of 81	ENSP00000479451.1	Q7Z6Z7-3

Frequencies

GnomAD3 genomes AF: 0.0187 AC: 2068 AN: 110497 Hom.: 26 Cov.: 22

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00437

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000757

Gnomad FIN AF: 0.0129

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0266

Gnomad OTH AF: 0.0305

GnomAD2 exomes AF: 0.0177 AC: 3236 AN: 182765 AF XY: 0.0171

Gnomad AFR exome AF: 0.00320

Gnomad AMR exome AF: 0.0102

Gnomad ASJ exome AF: 0.0765

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0274

GnomAD4 exome AF: 0.0241 AC: 26137 AN: 1086659 Hom.: 294 Cov.: 26 AF XY: 0.0228 AC XY: 8068 AN XY: 353459

African (AFR) AF: 0.00320 AC: 84 AN: 26230

American (AMR) AF: 0.0107 AC: 377 AN: 35139

Ashkenazi Jewish (ASJ) AF: 0.0746 AC: 1438 AN: 19281

East Asian (EAS) AF: 0.00 AC: 0 AN: 30085

South Asian (SAS) AF: 0.000781 AC: 42 AN: 53750

European-Finnish (FIN) AF: 0.0125 AC: 505 AN: 40415

Middle Eastern (MID) AF: 0.0141 AC: 58 AN: 4102

European-Non Finnish (NFE) AF: 0.0271 AC: 22519 AN: 831985

Other (OTH) AF: 0.0244 AC: 1114 AN: 45672

GnomAD4 genome AF: 0.0187 AC: 2067 AN: 110542 Hom.: 26 Cov.: 22 AF XY: 0.0172 AC XY: 565 AN XY: 32774

African (AFR) AF: 0.00305 AC: 93 AN: 30494

American (AMR) AF: 0.0231 AC: 239 AN: 10327

Ashkenazi Jewish (ASJ) AF: 0.0779 AC: 205 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.000380 AC: 1 AN: 2631

European-Finnish (FIN) AF: 0.0129 AC: 73 AN: 5638

Middle Eastern (MID) AF: 0.0141 AC: 3 AN: 213

European-Non Finnish (NFE) AF: 0.0266 AC: 1405 AN: 52872

Other (OTH) AF: 0.0302 AC: 45 AN: 1491

Alfa AF: 0.0247 Hom.: 1097

Bravo AF: 0.0189

ESP6500AA AF: 0.00391 AC: 15

ESP6500EA AF: 0.0275 AC: 185

ExAC AF: 0.0167 AC: 2023

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.2
DANN	Benign	0.24
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.52	N
PhyloP100		1.0
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.71	N
REVEL	Benign	0.024
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.037
MPC		0.75
ClinPred		0.0028	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.23
Mutation Taster		=97/3	polymorphism (auto)

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: rs41307640; hg19: chrX-53654402; COSMIC: COSV107261213; COSMIC: COSV107261213;