dbSNP rs61748839: HECTD4:p.Ala4242Ala (chr12-112163713-C-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001388303.1(HECTD4):c.12726G>T(p.Ala4242Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A4242A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HECTD4
NM_001388303.1 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.54

Publications

1 publications found

Variant links:

Genes affected

HECTD4 (HGNC:26611): (HECT domain E3 ubiquitin protein ligase 4) Predicted to enable ubiquitin-protein transferase activity. Involved in glucose homeostasis and glucose metabolic process. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

HECTD4 Gene-Disease associations (from GenCC):

neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Broad Center for Mendelian Genomics, G2P, Ambry Genetics, Baylor College of Medicine Research Center, Labcorp Genetics (formerly Invitae)

HECTD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP7

Synonymous conserved (PhyloP=-3.54 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001388303.1. 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
	HECTD4	NM_001388303.1	MANE Select	c.12726G>T	p.Ala4242Ala	synonymous	Exon 74 of 76	NP_001375232.1	A0A804HJX8
	HECTD4	NM_001109662.4		c.12756G>T	p.Ala4252Ala	synonymous	Exon 74 of 76	NP_001103132.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HECTD4	ENST00000682272.1	MANE Select	c.12726G>T	p.Ala4242Ala	synonymous	Exon 74 of 76	ENSP00000507687.1	A0A804HJX8
HECTD4	ENST00000377560.9	TSL:5	c.12720G>T	p.Ala4240Ala	synonymous	Exon 74 of 76	ENSP00000366783.7	J3KPF0
HECTD4	ENST00000550722.5	TSL:5	c.12324G>T	p.Ala4108Ala	synonymous	Exon 74 of 76	ENSP00000449784.2	F8VWT9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1338014

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

654798

African (AFR)

AF:

0.00

AC:

AN:

29488

American (AMR)

AF:

0.00

AC:

AN:

26884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21442

East Asian (EAS)

AF:

0.00

AC:

AN:

34208

South Asian (SAS)

AF:

0.00

AC:

AN:

70034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3778

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1050696

Other (OTH)

AF:

0.00

AC:

AN:

55096

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.022

(source)

DANN

Benign

0.67

PhyloP100

-3.5

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over