rs866255

Positions:

• chr10-68014084-G-A
• chr10-68014084-G-C
• chr10-68014084-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_015601.4(HERC4):​c.1011C>T​(p.Ser337=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.369 in 1,611,320 control chromosomes in the GnomAD database, including 119,154 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 0.38 (12108 hom., cov: 31)
  • Exomes 𝑓: 0.37 (107046 hom.)
• Consequence: HERC4 NM_015601.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=1.48 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC4	NM_015601.4	c.1011C>T	p.Ser337=	synonymous_variant	9/25	ENST00000373700.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC4	ENST00000373700.9	c.1011C>T	p.Ser337=	synonymous_variant	9/25	1	NM_015601.4	P4

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58410 AN: 151744 Hom.: 12089 Cov.: 31

Gnomad AFR AF: 0.392

Gnomad AMI AF: 0.471

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.848

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.437 AC: 109631 AN: 250934 Hom.: 27173 AF XY: 0.434 AC XY: 58827 AN XY: 135634

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.567

Gnomad ASJ exome AF: 0.310

Gnomad EAS exome AF: 0.853

Gnomad SAS exome AF: 0.552

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.388

GnomAD4 exome AF: 0.368 AC: 536718 AN: 1459458 Hom.: 107046 Cov.: 33 AF XY: 0.372 AC XY: 269877 AN XY: 726168

Gnomad4 AFR exome AF: 0.384

Gnomad4 AMR exome AF: 0.546

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.837

Gnomad4 SAS exome AF: 0.551

Gnomad4 FIN exome AF: 0.403

Gnomad4 NFE exome AF: 0.328

Gnomad4 OTH exome AF: 0.375

GnomAD4 genome AF: 0.385 AC: 58466 AN: 151862 Hom.: 12108 Cov.: 31 AF XY: 0.393 AC XY: 29175 AN XY: 74232

Gnomad4 AFR AF: 0.392

Gnomad4 AMR AF: 0.434

Gnomad4 ASJ AF: 0.316

Gnomad4 EAS AF: 0.848

Gnomad4 SAS AF: 0.545

Gnomad4 FIN AF: 0.409

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.384

Alfa AF: 0.334 Hom.: 13058

Bravo AF: 0.391

Asia WGS AF: 0.613 AC: 2129 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.308

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.3
DANN	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs866255; hg19: chr10-69773841; COSMIC: COSV53275924; COSMIC: COSV53275924;