4-88385507-T-C

Variant names:

• chr4-88385507-T-C
• rs7677237
• NM_017912.4:c.368T>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017912.4. 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
	HERC6	NM_017912.4	MANE Select	c.368T>C	p.Met123Thr	missense	Exon 3 of 23	NP_060382.3
	HERC6	NM_001165136.2		c.368T>C	p.Met123Thr	missense	Exon 3 of 22	NP_001158608.1	Q8IVU3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC6	ENST00000264346.12	TSL:1 MANE Select	c.368T>C	p.Met123Thr	missense	Exon 3 of 23	ENSP00000264346.8	Q8IVU3-1
	HERC6	ENST00000380265.9	TSL:1	c.368T>C	p.Met123Thr	missense	Exon 3 of 22	ENSP00000369617.5	Q8IVU3-2
	HERC6	ENST00000896956.1		c.368T>C	p.Met123Thr	missense	Exon 3 of 24	ENSP00000567015.1

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

GnomAD2 exomes AF: 0.0588 AC: 7634 AN: 129932 AF XY: 0.0551

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 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

African (AFR) AF: 0.210 AC: 5717 AN: 27168

American (AMR) AF: 0.0545 AC: 1409 AN: 25856

Ashkenazi Jewish (ASJ) AF: 0.0863 AC: 2039 AN: 23624

East Asian (EAS) AF: 0.000146 AC: 5 AN: 34276

South Asian (SAS) AF: 0.0259 AC: 1840 AN: 71146

European-Finnish (FIN) AF: 0.0476 AC: 2331 AN: 48974

Middle Eastern (MID) AF: 0.141 AC: 760 AN: 5372

European-Non Finnish (NFE) AF: 0.0530 AC: 51896 AN: 978606

Other (OTH) AF: 0.0656 AC: 3493 AN: 53278

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

African (AFR) AF: 0.212 AC: 8793 AN: 41472

American (AMR) AF: 0.0742 AC: 1134 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0863 AC: 299 AN: 3464

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0222 AC: 107 AN: 4828

European-Finnish (FIN) AF: 0.0518 AC: 549 AN: 10590

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3899 AN: 68018

Other (OTH) AF: 0.108 AC: 229 AN: 2112

Alfa AF: 0.0701 Hom.: 1483

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 v4.9

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
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.097	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.3	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.57	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.0070
MPC		0.18
ClinPred		0.00030	T
GERP RS		3.8
Varity_R		0.048
gMVP		0.11
Mutation Taster		=98/2	polymorphism (auto)

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: rs7677237; hg19: chr4-89306659;