rs1426444967

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr10-67932731-C-T
• chr10-67932731-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015601.4(HERC4):​c.2704G>A​(p.Ala902Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: HERC4 NM_015601.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26721847).

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>A	p.Ala902Thr	missense	Exon 23 of 25	NP_056416.2
	HERC4	NM_022079.3		c.2728G>A	p.Ala910Thr	missense	Exon 24 of 26	NP_071362.1	Q5GLZ8-1
	HERC4	NM_001278185.2		c.2494G>A	p.Ala832Thr	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>A	p.Ala902Thr	missense	Exon 23 of 25	ENSP00000362804.4	Q5GLZ8-2
	HERC4	ENST00000395198.7	TSL:1	c.2728G>A	p.Ala910Thr	missense	Exon 24 of 26	ENSP00000378624.3	Q5GLZ8-1
	HERC4	ENST00000412272.6	TSL:1	c.2494G>A	p.Ala832Thr	missense	Exon 22 of 24	ENSP00000416504.2	Q5GLZ8-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15276

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: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.11
Sift	Benign	0.12	T
Sift4G	Benign	0.20	T
Polyphen		0.36	B
Vest4		0.54
MutPred		0.43		Gain of catalytic residue at F913 (P = 0.1957)
MVP		0.21
MPC		1.1
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.23
gMVP		0.47
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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;