12-112279196-C-T

Variant names:

• chr12-112279196-C-T
• rs10492015
• NM_001388303.1:c.1687+32G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001388303.1(HECTD4):​c.1687+32G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 1,575,780 control chromosomes in the GnomAD database, including 10,760 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 0.056 (1293 hom., cov: 33)
  • Exomes 𝑓: 0.032 (9467 hom.)
• Consequence: HECTD4 NM_001388303.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.486
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Baylor College of Medicine Research Center, Broad Center for Mendelian Genomics, Ambry Genetics, G2P

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD4	NM_001388303.1	c.1687+32G>A		intron_variant	Intron 9 of 75	ENST00000682272.1	NP_001375232.1
HECTD4	NM_001109662.4	c.1687+32G>A		intron_variant	Intron 9 of 75		NP_001103132.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1	c.1687+32G>A		intron_variant	Intron 9 of 75		NM_001388303.1	ENSP00000507687.1
HECTD4	ENST00000377560.9	c.1687+32G>A		intron_variant	Intron 9 of 75	5		ENSP00000366783.7
HECTD4	ENST00000550722.5	c.1255+32G>A		intron_variant	Intron 9 of 75	5		ENSP00000449784.2
HECTD4	ENST00000550724.2	n.320-9347G>A		intron_variant	Intron 2 of 4	3		ENSP00000448061.2

Frequencies

GnomAD3 genomes AF: 0.0558 AC: 8475 AN: 152010 Hom.: 1298 Cov.: 33

Gnomad AFR AF: 0.0544

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.0643

GnomAD2 exomes AF: 0.0873 AC: 19869 AN: 227716 AF XY: 0.0786

Gnomad AFR exome AF: 0.0542

Gnomad AMR exome AF: 0.215

Gnomad ASJ exome AF: 0.00452

Gnomad EAS exome AF: 0.641

Gnomad FIN exome AF: 0.00367

Gnomad NFE exome AF: 0.00365

Gnomad OTH exome AF: 0.0512

GnomAD4 exome AF: 0.0323 AC: 46055 AN: 1423652 Hom.: 9467 Cov.: 26 AF XY: 0.0327 AC XY: 23203 AN XY: 709242

African (AFR) AF: 0.0507 AC: 1609 AN: 31752

American (AMR) AF: 0.200 AC: 7369 AN: 36864

Ashkenazi Jewish (ASJ) AF: 0.00486 AC: 123 AN: 25284

East Asian (EAS) AF: 0.639 AC: 24981 AN: 39064

South Asian (SAS) AF: 0.0760 AC: 6144 AN: 80846

European-Finnish (FIN) AF: 0.00324 AC: 172 AN: 53078

Middle Eastern (MID) AF: 0.0348 AC: 197 AN: 5664

European-Non Finnish (NFE) AF: 0.00237 AC: 2584 AN: 1092128

Other (OTH) AF: 0.0488 AC: 2876 AN: 58972

GnomAD4 genome AF: 0.0557 AC: 8480 AN: 152128 Hom.: 1293 Cov.: 33 AF XY: 0.0622 AC XY: 4629 AN XY: 74384

African (AFR) AF: 0.0543 AC: 2255 AN: 41500

American (AMR) AF: 0.144 AC: 2197 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.611 AC: 3150 AN: 5158

South Asian (SAS) AF: 0.0976 AC: 470 AN: 4818

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10582

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68008

Other (OTH) AF: 0.0636 AC: 134 AN: 2106

Alfa AF: 0.0204 Hom.: 189

Bravo AF: 0.0709

Asia WGS AF: 0.243 AC: 843 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.51
DANN	Benign	0.76
PhyloP100		-0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Mutation Taster		=100/0	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: rs10492015; hg19: chr12-112717000; COSMIC: COSV66398281;