chr12-112163079-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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]

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.13083G>A	p.Pro4361Pro	synonymous	Exon 75 of 76	NP_001375232.1	A0A804HJX8
	HECTD4	NM_001109662.4		c.13113G>A	p.Pro4371Pro	synonymous	Exon 75 of 76	NP_001103132.4
	MIR6861	NR_106921.1		n.*179G>A		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HECTD4	ENST00000682272.1	MANE Select	c.13083G>A	p.Pro4361Pro	synonymous	Exon 75 of 76	ENSP00000507687.1	A0A804HJX8
	HECTD4	ENST00000377560.9	TSL:5	c.13077G>A	p.Pro4359Pro	synonymous	Exon 75 of 76	ENSP00000366783.7	J3KPF0
	HECTD4	ENST00000550722.5	TSL:5	c.12681G>A	p.Pro4227Pro	synonymous	Exon 75 of 76	ENSP00000449784.2	F8VWT9

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

GnomAD2 exomes AF: 0.00623 AC: 1548 AN: 248352 AF XY: 0.00665

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 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

African (AFR) AF: 0.00122 AC: 41 AN: 33476

American (AMR) AF: 0.00101 AC: 45 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 31 AN: 26078

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39696

South Asian (SAS) AF: 0.00413 AC: 356 AN: 86220

European-Finnish (FIN) AF: 0.0152 AC: 811 AN: 53362

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5762

European-Non Finnish (NFE) AF: 0.00774 AC: 8600 AN: 1111588

Other (OTH) AF: 0.00495 AC: 299 AN: 60352

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

African (AFR) AF: 0.00147 AC: 61 AN: 41406

American (AMR) AF: 0.00144 AC: 22 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.000778 AC: 4 AN: 5144

South Asian (SAS) AF: 0.00561 AC: 27 AN: 4814

European-Finnish (FIN) AF: 0.0177 AC: 187 AN: 10542

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

European-Non Finnish (NFE) AF: 0.00717 AC: 487 AN: 67940

Other (OTH) AF: 0.00474 AC: 10 AN: 2110

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.58
DANN	Benign	0.61
PhyloP100		-9.4
Mutation Taster		=89/11	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: rs183882784; hg19: chr12-112600883;