10-67932731-C-A

Variant names:

• chr10-67932731-C-A
• rs1426444967
• NM_015601.4:c.2704G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015601.4(HERC4):​c.2704G>T​(p.Ala902Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A902T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HERC4 NM_015601.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96
• Publications: 0 publications found

Genes affected

HERC4 (HGNC:24521): (HECT and RLD domain containing E3 ubiquitin protein ligase 4) HERC4 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22665444).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015601.4. 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
	HERC4	NM_015601.4	MANE Select	c.2704G>T	p.Ala902Ser	missense	Exon 23 of 25	NP_056416.2
	HERC4	NM_022079.3		c.2728G>T	p.Ala910Ser	missense	Exon 24 of 26	NP_071362.1	Q5GLZ8-1
	HERC4	NM_001278185.2		c.2494G>T	p.Ala832Ser	missense	Exon 22 of 24	NP_001265114.1	Q5GLZ8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HERC4	ENST00000373700.9	TSL:1 MANE Select	c.2704G>T	p.Ala902Ser	missense	Exon 23 of 25	ENSP00000362804.4	Q5GLZ8-2
	HERC4	ENST00000395198.7	TSL:1	c.2728G>T	p.Ala910Ser	missense	Exon 24 of 26	ENSP00000378624.3	Q5GLZ8-1
	HERC4	ENST00000412272.6	TSL:1	c.2494G>T	p.Ala832Ser	missense	Exon 22 of 24	ENSP00000416504.2	Q5GLZ8-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451154 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721736

African (AFR) AF: 0.00 AC: 0 AN: 32620

American (AMR) AF: 0.00 AC: 0 AN: 40948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 83468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109682

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.089	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.52	N
PhyloP100		5.0
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.13
Sift	Benign	0.19	T
Sift4G	Benign	0.34	T
Polyphen		0.022	B
Vest4		0.56
MutPred		0.48		Loss of catalytic residue at A910 (P = 0.028)
MVP		0.21
MPC		0.79
ClinPred		0.80	D
GERP RS		5.2
Varity_R		0.22
gMVP		0.43
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1426444967; hg19: chr10-69692488;