14-31178035-G-A

Variant names:

• chr14-31178035-G-A
• rs2274201
• NM_015382.4:c.360C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.405
• Publications: 22 publications found

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

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015382.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECTD1	NM_015382.4	MANE Select	c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	NP_056197.3
	HECTD1	NM_001437347.1		c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	NP_001424276.1
	HECTD1	NM_001439059.1		c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	NP_001425988.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECTD1	ENST00000399332.6	TSL:5 MANE Select	c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	ENSP00000382269.1
	HECTD1	ENST00000553700.5	TSL:5	c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	ENSP00000450697.1
	HECTD1	ENST00000611816.5	TSL:5	c.360C>T	p.Ala120Ala	synonymous	Exon 3 of 43	ENSP00000484981.2

Frequencies

GnomAD3 genomes AF: 0.502 AC: 76201 AN: 151738 Hom.: 20313 Cov.: 31

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

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.: 33 AF XY: 0.424 AC XY: 307277 AN XY: 725204

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

GnomAD4 genome AF: 0.503 AC: 76316 AN: 151860 Hom.: 20360 Cov.: 31 AF XY: 0.500 AC XY: 37116 AN XY: 74200

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

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

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.6
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)

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: rs2274201; hg19: chr14-31647241; COSMIC: COSV67945562; COSMIC: COSV67945562;