4-88385507-T-C

Position:

• chr4-88385507-T-C

Variant summary

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

The NM_017912.4(HERC6):​c.368T>C​(p.Met123Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0596 in 1,420,464 control chromosomes in the GnomAD database, including 3,655 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.10 (1136 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2519 hom.)
• Consequence: HERC6 NM_017912.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.21

Genes affected

HERC6 (HGNC:26072): (HECT and RLD domain containing E3 ubiquitin protein ligase family member 6) HERC6 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 (MetaRNN=0.0023404658).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HERC6	NM_017912.4	c.368T>C	p.Met123Thr	missense_variant	3/23	ENST00000264346.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HERC6	ENST00000264346.12	c.368T>C	p.Met123Thr	missense_variant	3/23	1	NM_017912.4	P1

Frequencies

GnomAD3 genomes AF: 0.0997 AC: 15156 AN: 152046 Hom.: 1135 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.0743

Gnomad ASJ AF: 0.0863

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.0518

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.110

GnomAD3 exomes AF: 0.0588 AC: 7634 AN: 129932 Hom.: 337 AF XY: 0.0551 AC XY: 3805 AN XY: 69086

Gnomad AFR exome AF: 0.211

Gnomad AMR exome AF: 0.0488

Gnomad ASJ exome AF: 0.0858

Gnomad EAS exome AF: 0.000347

Gnomad SAS exome AF: 0.0259

Gnomad FIN exome AF: 0.0497

Gnomad NFE exome AF: 0.0592

Gnomad OTH exome AF: 0.0726

GnomAD4 exome AF: 0.0548 AC: 69490 AN: 1268300 Hom.: 2519 Cov.: 19 AF XY: 0.0540 AC XY: 34087 AN XY: 630882

Gnomad4 AFR exome AF: 0.210

Gnomad4 AMR exome AF: 0.0545

Gnomad4 ASJ exome AF: 0.0863

Gnomad4 EAS exome AF: 0.000146

Gnomad4 SAS exome AF: 0.0259

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0530

Gnomad4 OTH exome AF: 0.0656

GnomAD4 genome AF: 0.0998 AC: 15182 AN: 152164 Hom.: 1136 Cov.: 32 AF XY: 0.0970 AC XY: 7218 AN XY: 74404

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.0742

Gnomad4 ASJ AF: 0.0863

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0222

Gnomad4 FIN AF: 0.0518

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.108

Alfa AF: 0.0633 Hom.: 980

Bravo AF: 0.106

TwinsUK AF: 0.0547 AC: 203

ALSPAC AF: 0.0553 AC: 213

ESP6500AA AF: 0.187 AC: 646

ESP6500EA AF: 0.0526 AC: 406

ExAC AF: 0.0313 AC: 2713

Asia WGS AF: 0.0280 AC: 98 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	4.9
DANN	Benign	0.55
DEOGEN2	Benign	0.0017	T;.;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.097	T;T;T
MetaRNN	Benign	0.0023	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	.;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.57	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.48	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.0070
MPC		0.18
ClinPred		0.00030	T
GERP RS		3.8
Varity_R		0.048
gMVP		0.11

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: rs7677237; hg19: chr4-89306659;