dbSNP rs2274201: HECTD1:p.Ala120Ala (chr14-31178035-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_015382.4(HECTD1):c.360C>T(p.Ala120Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 1,609,034 control chromosomes in the GnomAD database, including 154,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 20360 hom., cov: 31)

Exomes 𝑓: 0.42 ( 134311 hom. )

Consequence

HECTD1
NM_015382.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.405

Publications

22 publications found

Variant links:

Genes affected

HECTD1 (HGNC:20157): (HECT domain E3 ubiquitin protein ligase 1) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in anatomical structure development; positive regulation of proteasomal ubiquitin-dependent protein catabolic process; and protein K63-linked ubiquitination. Predicted to act upstream of or within several processes, including animal organ development; negative regulation of protein localization to plasma membrane; and protein autoubiquitination. [provided by Alliance of Genome Resources, Apr 2022]

HECTD1 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
neural tube defect
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

HECTD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 14-31178035-G-A is Benign according to our data. Variant chr14-31178035-G-A is described in ClinVar as Benign. ClinVar VariationId is 1178217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.405 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD1	NM_015382.4 link	c.360C>T	p.Ala120Ala	synonymous_variant	Exon 3 of 43	ENST00000399332.6	NP_056197.3	Q9ULT8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD1	ENST00000399332.6 link	c.360C>T	p.Ala120Ala	synonymous_variant	Exon 3 of 43	5	NM_015382.4	ENSP00000382269.1		Q9ULT8

Frequencies

GnomAD3 genomes

AF:

0.502

AC:

76201

AN:

151738

Hom.:

20313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.685

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.535

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.441

Gnomad SAS

AF:

0.518

Gnomad FIN

AF:

0.413

Gnomad MID

AF:

0.401

Gnomad NFE

AF:

0.411

Gnomad OTH

AF:

0.485

GnomAD2 exomes

AF:

0.473

AC:

117830

AN:

249372

AF XY:

0.462

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.649

Gnomad ASJ exome

AF:

0.376

Gnomad EAS exome

AF:

0.432

Gnomad FIN exome

AF:

0.418

Gnomad NFE exome

AF:

0.410

Gnomad OTH exome

AF:

0.441

GnomAD4 exome

AF:

0.423

AC:

616810

AN:

1457174

Hom.:

134311

Cov.:

AF XY:

0.424

AC XY:

307277

AN XY:

725204

show subpopulations

African (AFR)

AF:

0.694

AC:

23154

AN:

33386

American (AMR)

AF:

0.635

AC:

28407

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

9784

AN:

26096

East Asian (EAS)

AF:

0.431

AC:

17095

AN:

39668

South Asian (SAS)

AF:

0.496

AC:

42730

AN:

86140

European-Finnish (FIN)

AF:

0.426

AC:

22746

AN:

53408

Middle Eastern (MID)

AF:

0.391

AC:

2254

AN:

5760

European-Non Finnish (NFE)

AF:

0.402

AC:

444791

AN:

1107740

Other (OTH)

AF:

0.429

AC:

25849

AN:

60260

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

15556

31112

46669

62225

77781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13924

27848

41772

55696

69620

<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:

0.503

AC:

76316

AN:

151860

Hom.:

20360

Cov.:

AF XY:

0.500

AC XY:

37116

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.685

AC:

28398

AN:

41438

American (AMR)

AF:

0.536

AC:

8165

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1297

AN:

3470

East Asian (EAS)

AF:

0.441

AC:

2276

AN:

5156

South Asian (SAS)

AF:

0.518

AC:

2489

AN:

4802

European-Finnish (FIN)

AF:

0.413

AC:

4344

AN:

10512

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.411

AC:

27924

AN:

67942

Other (OTH)

AF:

0.483

AC:

1017

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1833

3666

5499

7332

9165

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<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:

0.439

Hom.:

30905

Bravo

AF:

0.519

Asia WGS

AF:

0.477

AC:

1658

AN:

3478

EpiCase

AF:

0.399

EpiControl

AF:

0.394

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 05, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.6

(source)

DANN

Benign

0.73

PhyloP100

0.41

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=89/11

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over