12-112163079-C-T

Variant names:

• chr12-112163079-C-T
• rs183882784
• NM_001388303.1:c.13083G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001388303.1(HECTD4):​c.13083G>A​(p.Pro4361Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00685 in 1,613,118 control chromosomes in the GnomAD database, including 61 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (57 hom.)
• Consequence: HECTD4 NM_001388303.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -9.36

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]

MIR6861 (HGNC:50129): (microRNA 6861) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 12-112163079-C-T is Benign according to our data. Variant chr12-112163079-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 773266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-9.36 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0053 (805/151894) while in subpopulation NFE AF= 0.00717 (487/67940). AF 95% confidence interval is 0.00664. There are 4 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HECTD4	NM_001388303.1	c.13083G>A	p.Pro4361Pro	synonymous_variant	Exon 75 of 76	ENST00000682272.1	NP_001375232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HECTD4	ENST00000682272.1	c.13083G>A	p.Pro4361Pro	synonymous_variant	Exon 75 of 76		NM_001388303.1	ENSP00000507687.1

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 806 AN: 151776 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00148

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.0177

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00717

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00623 AC: 1548 AN: 248352 Hom.: 9 AF XY: 0.00665 AC XY: 896 AN XY: 134718

Gnomad AFR exome AF: 0.00129

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.000723

Gnomad SAS exome AF: 0.00478

Gnomad FIN exome AF: 0.0149

Gnomad NFE exome AF: 0.00857

Gnomad OTH exome AF: 0.00565

GnomAD4 exome AF: 0.00701 AC: 10242 AN: 1461224 Hom.: 57 Cov.: 32 AF XY: 0.00706 AC XY: 5130 AN XY: 726890

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00101

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.00413

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.00774

Gnomad4 OTH exome AF: 0.00495

GnomAD4 genome AF: 0.00530 AC: 805 AN: 151894 Hom.: 4 Cov.: 32 AF XY: 0.00610 AC XY: 453 AN XY: 74240

Gnomad4 AFR AF: 0.00147

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000778

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.0177

Gnomad4 NFE AF: 0.00717

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00601 Hom.: 4

Bravo AF: 0.00385

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HECTD4: BP4, BP7 -

Jun 23, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.58
DANN	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs183882784; hg19: chr12-112600883;