rs497849

Positions:

• chr10-67993863-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_015601.4(HERC4):​c.1070-1181G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,182 control chromosomes in the GnomAD database, including 2,061 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 0.14 (2061 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: HERC4 NM_015601.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.125

Genes affected

HERC4 (HGNC:24521): (HECT and RLD domain containing E3 ubiquitin protein ligase 4) HERC4 belongs to the HERC family of ubiquitin ligases, all of which contain a HECT domain and at least 1 RCC1 (MIM 179710)-like domain (RLD). The 350-amino acid HECT domain is predicted to catalyze the formation of a thioester with ubiquitin before transferring it to a substrate, and the RLD is predicted to act as a guanine nucleotide exchange factor for small G proteins (Hochrainer et al., 2005 [PubMed 15676274]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HERC4	NM_015601.4	c.1070-1181G>A		intron_variant		ENST00000373700.9	NP_056416.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HERC4	ENST00000373700.9	c.1070-1181G>A		intron_variant		1	NM_015601.4	ENSP00000362804	P4

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21628 AN: 152060 Hom.: 2062 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.140

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.142 AC: 21621 AN: 152178 Hom.: 2061 Cov.: 32 AF XY: 0.137 AC XY: 10159 AN XY: 74402

Gnomad4 AFR AF: 0.0412

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0431

Gnomad4 FIN AF: 0.168

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.137

Alfa AF: 0.198 Hom.: 4876

Bravo AF: 0.134

Asia WGS AF: 0.0250 AC: 90 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.6
DANN	Benign	0.27

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: rs497849; hg19: chr10-69753620;