Genetic Variant HECTD4:c.11595-49C>T (chr12-112172910-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001388303.1(HECTD4):c.11595-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,503,978 control chromosomes in the GnomAD database, including 111,020 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 8493 hom., cov: 32)

Exomes 𝑓: 0.37 ( 102527 hom. )

Consequence

HECTD4
NM_001388303.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.12

Publications

61 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: Labcorp Genetics (formerly Invitae), Baylor College of Medicine Research Center, Broad Center for Mendelian Genomics, Ambry Genetics, G2P

HECTD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.416 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD4	NM_001388303.1 link	c.11595-49C>T		intron_variant	Intron 66 of 75	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4 link	c.11625-49C>T		intron_variant	Intron 66 of 75		NP_001103132.4	F8VWT9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1 link	c.11595-49C>T		intron_variant	Intron 66 of 75		NM_001388303.1	ENSP00000507687.1		A0A804HJX8

Frequencies

GnomAD3 genomes

AF:

0.284

AC:

43123

AN:

151954

Hom.:

8498

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0698

Gnomad AMI

AF:

0.398

Gnomad AMR

AF:

0.259

Gnomad ASJ

AF:

0.652

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0775

Gnomad FIN

AF:

0.376

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.314

GnomAD2 exomes

AF:

0.300

AC:

73161

AN:

243690

AF XY:

0.302

show subpopulations

Gnomad AFR exome

AF:

0.0576

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.635

Gnomad EAS exome

AF:

0.000502

Gnomad FIN exome

AF:

0.377

Gnomad NFE exome

AF:

0.426

Gnomad OTH exome

AF:

0.365

GnomAD4 exome

AF:

0.368

AC:

497731

AN:

1351906

Hom.:

102527

Cov.:

AF XY:

0.363

AC XY:

245219

AN XY:

676114

show subpopulations

African (AFR)

AF:

0.0566

AC:

1773

AN:

31318

American (AMR)

AF:

0.207

AC:

9184

AN:

44376

Ashkenazi Jewish (ASJ)

AF:

0.631

AC:

15902

AN:

25214

East Asian (EAS)

AF:

0.000487

AC:

AN:

39038

South Asian (SAS)

AF:

0.0916

AC:

7657

AN:

83634

European-Finnish (FIN)

AF:

0.378

AC:

19617

AN:

51886

Middle Eastern (MID)

AF:

0.321

AC:

1714

AN:

5344

European-Non Finnish (NFE)

AF:

0.416

AC:

421884

AN:

1014512

Other (OTH)

AF:

0.353

AC:

19981

AN:

56584

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

14734

29469

44203

58938

73672

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11924

23848

35772

47696

59620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.283

AC:

43101

AN:

152072

Hom.:

8493

Cov.:

AF XY:

0.275

AC XY:

20444

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0696

AC:

2887

AN:

41504

American (AMR)

AF:

0.258

AC:

3940

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.652

AC:

2260

AN:

3466

East Asian (EAS)

AF:

0.00174

AC:

AN:

5180

South Asian (SAS)

AF:

0.0774

AC:

373

AN:

4820

European-Finnish (FIN)

AF:

0.376

AC:

3987

AN:

10590

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.420

AC:

28524

AN:

67944

Other (OTH)

AF:

0.311

AC:

655

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1376

2751

4127

5502

6878

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.366

Hom.:

11972

Bravo

AF:

0.270

Asia WGS

AF:

0.0510

AC:

177

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.1

(source)

DANN

Benign

0.59

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over