NM_001388303.1:c.12726G>A

Variant names:

• chr12-112163713-C-T
• rs61748839
• NM_001388303.1:c.12726G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.54
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 25 AR gene

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>A	p.Ala4242Ala	synonymous	Exon 74 of 76	NP_001375232.1	A0A804HJX8
	HECTD4	NM_001109662.4		c.12756G>A	p.Ala4252Ala	synonymous	Exon 74 of 76	NP_001103132.4

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152200 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.00423 AC: 415 AN: 98208 AF XY: 0.00394

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 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.: 25 Cov.: 33 AF XY: 0.00367 AC XY: 2406 AN XY: 654790

African (AFR) AF: 0.000271 AC: 8 AN: 29488

American (AMR) AF: 0.000744 AC: 20 AN: 26884

Ashkenazi Jewish (ASJ) AF: 0.0000466 AC: 1 AN: 21442

East Asian (EAS) AF: 0.0000292 AC: 1 AN: 34208

South Asian (SAS) AF: 0.000129 AC: 9 AN: 70036

European-Finnish (FIN) AF: 0.0191 AC: 884 AN: 46384

Middle Eastern (MID) AF: 0.000265 AC: 1 AN: 3778

European-Non Finnish (NFE) AF: 0.00389 AC: 4090 AN: 1050684

Other (OTH) AF: 0.00249 AC: 137 AN: 55096

GnomAD4 genome AF: 0.00381 AC: 581 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00419 AC XY: 312 AN XY: 74478

African (AFR) AF: 0.000553 AC: 23 AN: 41576

American (AMR) AF: 0.00124 AC: 19 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.0194 AC: 206 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00481 AC: 327 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00352 Hom.: 0

Bravo AF: 0.00229

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.40
DANN	Benign	0.72
PhyloP100		-3.5
Mutation Taster		=99/1	polymorphism

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: rs61748839; hg19: chr12-112601517; COSMIC: COSV101108409; COSMIC: COSV101108409;