4-88398144-T-G

Variant names:

• chr4-88398144-T-G
• rs17014118
• NM_017912.4:c.1027T>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017912.4(HERC6):​c.1027T>G​(p.Phe343Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000221 in 1,582,666 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F343L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: HERC6 NM_017912.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08285305).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HERC6	NM_017912.4	c.1027T>G	p.Phe343Val	missense_variant, splice_region_variant	Exon 8 of 23	ENST00000264346.12	NP_060382.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HERC6	ENST00000264346.12	c.1027T>G	p.Phe343Val	missense_variant, splice_region_variant	Exon 8 of 23	1	NM_017912.4	ENSP00000264346.8
HERC6	ENST00000380265.9	c.1027T>G	p.Phe343Val	missense_variant, splice_region_variant	Exon 8 of 22	1		ENSP00000369617.5
HERC6	ENST00000506714.5	n.855T>G		non_coding_transcript_exon_variant	Exon 7 of 8	2
HERC6	ENST00000515365.1	n.423T>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 6	3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000231 AC: 33 AN: 1430642 Hom.: 0 Cov.: 27 AF XY: 0.0000239 AC XY: 17 AN XY: 710170

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000292

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152024 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74252

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0025	.;T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.083	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.068
Sift	Benign	0.20	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.038	B;B
Vest4		0.17
MutPred		0.43		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.85
MPC		0.20
ClinPred		0.093	T
GERP RS		2.6
Varity_R		0.063
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs17014118; hg19: chr4-89319296;