rs7677237

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr4-88385507-T-A
• chr4-88385507-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017912.4(HERC6):​c.368T>A​(p.Met123Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000774 in 1,421,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000079 (0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.056232154).

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>A	p.Met123Lys	missense	Exon 3 of 23	NP_060382.3
	HERC6	NM_001165136.2		c.368T>A	p.Met123Lys	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>A	p.Met123Lys	missense	Exon 3 of 23	ENSP00000264346.8	Q8IVU3-1
	HERC6	ENST00000380265.9	TSL:1	c.368T>A	p.Met123Lys	missense	Exon 3 of 22	ENSP00000369617.5	Q8IVU3-2
	HERC6	ENST00000896956.1		c.368T>A	p.Met123Lys	missense	Exon 3 of 24	ENSP00000567015.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152092 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000787 AC: 10 AN: 1269892 Hom.: 0 Cov.: 19 AF XY: 0.00000317 AC XY: 2 AN XY: 631582

African (AFR) AF: 0.0000366 AC: 1 AN: 27294

American (AMR) AF: 0.00 AC: 0 AN: 25886

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23646

East Asian (EAS) AF: 0.00 AC: 0 AN: 34276

South Asian (SAS) AF: 0.00 AC: 0 AN: 71176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5384

European-Non Finnish (NFE) AF: 0.00000918 AC: 9 AN: 979904

Other (OTH) AF: 0.00 AC: 0 AN: 53334

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152092 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74306

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41378

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1483

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	1.5
DANN	Benign	0.56
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.5	N
PhyloP100		1.2
PrimateAI	Benign	0.38	T
PROVEAN	Benign	3.4	N
REVEL	Benign	0.22
Sift	Benign	1.0	T
Sift4G	Benign	0.91	T
Polyphen		0.0	B
Vest4		0.062
MutPred		0.49		Gain of disorder (P = 0.0391)
MVP		0.81
MPC		0.24
ClinPred		0.032	T
GERP RS		3.8
Varity_R		0.11
gMVP		0.14
Mutation Taster		=95/5	polymorphism

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;