4-88398144-T-C

Variant names:

• chr4-88398144-T-C
• rs17014118
• NM_017912.4:c.1027T>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.1027T>C​(p.Phe343Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,578,912 control chromosomes in the GnomAD database, including 64,465 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (15581 hom., cov: 32)
  • Exomes 𝑓: 0.21 (48884 hom.)
• Consequence: HERC6 NM_017912.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• Publications: 26 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=1.0141398E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.724 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.1027T>C	p.Phe343Leu	missense splice_region	Exon 8 of 23	NP_060382.3
	HERC6	NM_001165136.2		c.1027T>C	p.Phe343Leu	missense splice_region	Exon 8 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.1027T>C	p.Phe343Leu	missense splice_region	Exon 8 of 23	ENSP00000264346.8	Q8IVU3-1
	HERC6	ENST00000380265.9	TSL:1	c.1027T>C	p.Phe343Leu	missense splice_region	Exon 8 of 22	ENSP00000369617.5	Q8IVU3-2
	HERC6	ENST00000896956.1		c.1027T>C	p.Phe343Leu	missense splice_region	Exon 8 of 24	ENSP00000567015.1

Frequencies

GnomAD3 genomes AF: 0.373 AC: 56673 AN: 151966 Hom.: 15530 Cov.: 32

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.129

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.700

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.260

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.323

GnomAD2 exomes AF: 0.316 AC: 68228 AN: 216168 AF XY: 0.308

Gnomad AFR exome AF: 0.748

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.710

Gnomad FIN exome AF: 0.264

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.252

GnomAD4 exome AF: 0.209 AC: 298353 AN: 1426826 Hom.: 48884 Cov.: 27 AF XY: 0.215 AC XY: 152395 AN XY: 708330

African (AFR) AF: 0.753 AC: 24389 AN: 32380

American (AMR) AF: 0.422 AC: 16839 AN: 39856

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4114 AN: 25616

East Asian (EAS) AF: 0.728 AC: 28037 AN: 38520

South Asian (SAS) AF: 0.475 AC: 38183 AN: 80344

European-Finnish (FIN) AF: 0.261 AC: 13677 AN: 52420

Middle Eastern (MID) AF: 0.250 AC: 1421 AN: 5694

European-Non Finnish (NFE) AF: 0.143 AC: 156710 AN: 1092894

Other (OTH) AF: 0.254 AC: 14983 AN: 59102

GnomAD4 genome AF: 0.373 AC: 56793 AN: 152086 Hom.: 15581 Cov.: 32 AF XY: 0.383 AC XY: 28461 AN XY: 74348

African (AFR) AF: 0.731 AC: 30302 AN: 41468

American (AMR) AF: 0.368 AC: 5621 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3466

East Asian (EAS) AF: 0.700 AC: 3614 AN: 5166

South Asian (SAS) AF: 0.505 AC: 2429 AN: 4810

European-Finnish (FIN) AF: 0.260 AC: 2757 AN: 10586

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10614 AN: 67988

Other (OTH) AF: 0.324 AC: 682 AN: 2104

Alfa AF: 0.250 Hom.: 14006

Bravo AF: 0.396

TwinsUK AF: 0.143 AC: 531

ALSPAC AF: 0.142 AC: 546

ESP6500AA AF: 0.716 AC: 2599

ESP6500EA AF: 0.147 AC: 1194

ExAC AF: 0.309 AC: 37207

Asia WGS AF: 0.563 AC: 1953 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.3
DANN	Benign	0.60
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.0027	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.33
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.058
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MutPred		0.42		Loss of sheet (P = 0.0457)
MPC		0.18
ClinPred		0.00030	T
GERP RS		2.6
Varity_R		0.041
gMVP		0.17
Mutation Taster		=99/1	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: rs17014118; hg19: chr4-89319296; COSMIC: COSV52030107;