rs16924989

Positions:

• chr10-67954262-A-G
• chr10-67954262-A-T

Variant summary

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

The NM_015601.4(HERC4):​c.2337+333T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 175,894 control chromosomes in the GnomAD database, including 1,167 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 0.11 (971 hom., cov: 32)
  • Exomes 𝑓: 0.12 (196 hom.)
• Consequence: HERC4 NM_015601.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.91

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=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC4	NM_015601.4	c.2337+333T>C		intron_variant		ENST00000373700.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC4	ENST00000373700.9	c.2337+333T>C		intron_variant		1	NM_015601.4	P4

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16849 AN: 152084 Hom.: 971 Cov.: 32

Gnomad AFR AF: 0.0737

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.118

GnomAD4 exome AF: 0.119 AC: 2826 AN: 23692 Hom.: 196 Cov.: 0 AF XY: 0.119 AC XY: 1471 AN XY: 12330

Gnomad4 AFR exome AF: 0.0699

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.120

Gnomad4 SAS exome AF: 0.134

Gnomad4 FIN exome AF: 0.0833

Gnomad4 NFE exome AF: 0.123

Gnomad4 OTH exome AF: 0.124

GnomAD4 genome AF: 0.111 AC: 16864 AN: 152202 Hom.: 971 Cov.: 32 AF XY: 0.111 AC XY: 8247 AN XY: 74410

Gnomad4 AFR AF: 0.0737

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.0995

Gnomad4 NFE AF: 0.124

Gnomad4 OTH AF: 0.117

Alfa AF: 0.116 Hom.: 166

Bravo AF: 0.110

Asia WGS AF: 0.127 AC: 442 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.7
DANN	Benign	0.78

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: rs16924989; hg19: chr10-69714019;