NM_015601.4:c.2716G>A

Variant names:

• chr10-67932719-C-T
• rs143083420
• NM_015601.4:c.2716G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015601.4(HERC4):​c.2716G>A​(p.Asp906Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00203 in 1,600,054 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (16 hom.)
• Consequence: HERC4 NM_015601.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.43
• Publications: 5 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009596795).
• BP6: Variant 10-67932719-C-T is Benign according to our data. Variant chr10-67932719-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2640521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 350 AD gene.

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.2716G>A	p.Asp906Asn	missense	Exon 23 of 25	NP_056416.2
	HERC4	NM_022079.3		c.2740G>A	p.Asp914Asn	missense	Exon 24 of 26	NP_071362.1	Q5GLZ8-1
	HERC4	NM_001278185.2		c.2506G>A	p.Asp836Asn	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.2716G>A	p.Asp906Asn	missense	Exon 23 of 25	ENSP00000362804.4	Q5GLZ8-2
	HERC4	ENST00000395198.7	TSL:1	c.2740G>A	p.Asp914Asn	missense	Exon 24 of 26	ENSP00000378624.3	Q5GLZ8-1
	HERC4	ENST00000412272.6	TSL:1	c.2506G>A	p.Asp836Asn	missense	Exon 22 of 24	ENSP00000416504.2	Q5GLZ8-3

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152128 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00236 AC: 557 AN: 235546 AF XY: 0.00250

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00448

Gnomad NFE exome AF: 0.00267

Gnomad OTH exome AF: 0.00241

GnomAD4 exome AF: 0.00200 AC: 2902 AN: 1447808 Hom.: 16 Cov.: 31 AF XY: 0.00211 AC XY: 1522 AN XY: 719928

African (AFR) AF: 0.000865 AC: 28 AN: 32354

American (AMR) AF: 0.00183 AC: 73 AN: 39796

Ashkenazi Jewish (ASJ) AF: 0.00179 AC: 46 AN: 25714

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.00307 AC: 253 AN: 82504

European-Finnish (FIN) AF: 0.00360 AC: 192 AN: 53340

Middle Eastern (MID) AF: 0.00940 AC: 54 AN: 5746

European-Non Finnish (NFE) AF: 0.00191 AC: 2113 AN: 1108972

Other (OTH) AF: 0.00239 AC: 143 AN: 59900

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152246 Hom.: 3 Cov.: 33 AF XY: 0.00244 AC XY: 182 AN XY: 74448

African (AFR) AF: 0.000361 AC: 15 AN: 41546

American (AMR) AF: 0.00327 AC: 50 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00290 AC: 197 AN: 68010

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00234 Hom.: 1

Bravo AF: 0.00213

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00232 AC: 282

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00344

EpiControl AF: 0.00374

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		2.4
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.023
Sift	Benign	0.51	T
Sift4G	Benign	0.41	T
Polyphen		0.0020	B
Vest4		0.26
MVP		0.36
MPC		0.76
ClinPred		0.0089	T
GERP RS		5.2
Varity_R		0.059
gMVP		0.46
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs143083420; hg19: chr10-69692476;