Genetic Variant HECTD4:p.Ala4242Ala (chr12-112163713-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_001388303.1(HECTD4):c.12726G>A(p.Ala4242Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00385 in 1,490,318 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0038 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0038 ( 25 hom. )

Consequence

HECTD4
NM_001388303.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.54

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 12-112163713-C-T is Benign according to our data. Variant chr12-112163713-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2643334.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

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

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00381 (581/152318) while in subpopulation NFE AF= 0.00481 (327/68012). AF 95% confidence interval is 0.00438. There are 0 homozygotes in gnomad4. There are 312 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD4	NM_001388303.1 link	c.12726G>A	p.Ala4242Ala	synonymous_variant	Exon 74 of 76	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4 link	c.12756G>A	p.Ala4252Ala	synonymous_variant	Exon 74 of 76		NP_001103132.4	F8VWT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1 link	c.12726G>A	p.Ala4242Ala	synonymous_variant	Exon 74 of 76		NM_001388303.1	ENSP00000507687.1		A0A804HJX8

Frequencies

GnomAD3 genomes

AF:

0.00382

AC:

581

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0194

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00481

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00423

AC:

415

AN:

98208

Hom.:

AF XY:

0.00394

AC XY:

203

AN XY:

51508

show subpopulations

Gnomad AFR exome

AF:

0.000329

Gnomad AMR exome

AF:

0.000500

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000765

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.00394

Gnomad OTH exome

AF:

0.00357

GnomAD4 exome

AF:

0.00385

AC:

5151

AN:

1338000

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

2406

AN XY:

654790

show subpopulations

Gnomad4 AFR exome

AF:

0.000271

Gnomad4 AMR exome

AF:

0.000744

Gnomad4 ASJ exome

AF:

0.0000466

Gnomad4 EAS exome

AF:

0.0000292

Gnomad4 SAS exome

AF:

0.000129

Gnomad4 FIN exome

AF:

0.0191

Gnomad4 NFE exome

AF:

0.00389

Gnomad4 OTH exome

AF:

0.00249

GnomAD4 genome

AF:

0.00381

AC:

581

AN:

152318

Hom.:

Cov.:

AF XY:

0.00419

AC XY:

312

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000553

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0194

Gnomad4 NFE

AF:

0.00481

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00352

Hom.:

Bravo

AF:

0.00229

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HECTD4: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.40

DANN

Benign

0.72

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over