12-14829418-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_021071.4(ART4):c.898C>G(p.Leu300Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,606,268 control chromosomes in the GnomAD database, including 11,176 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.12 (1312 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9864 hom.)
• Consequence: ART4 NM_021071.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.332

Genes affected

ART4 (HGNC:726): (ADP-ribosyltransferase 4 (inactive) (Dombrock blood group)) This gene encodes a protein that contains a mono-ADP-ribosylation (ART) motif. It is a member of the ADP-ribosyltransferase gene family but enzymatic activity has not been demonstrated experimentally. Antigens of the Dombrock blood group system are located on the gene product, which is glycosylphosphatidylinosotol-anchored to the erythrocyte membrane. Allelic variants, some of which lead to adverse transfusion reactions, are known. [provided by RefSeq, Jul 2008]

C12orf60 (HGNC:28726): (chromosome 12 open reading frame 60)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039037168).
• BP6: Variant 12-14829418-G-C is Benign according to our data. Variant chr12-14829418-G-C is described in ClinVar as [Benign]. Clinvar id is 3060827.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.22 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ART4	NM_021071.4	c.898C>G	p.Leu300Val	missense_variant	3/3	ENST00000228936.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ART4	ENST00000228936.6	c.898C>G	p.Leu300Val	missense_variant	3/3	1	NM_021071.4	P1

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18240 AN: 152010 Hom.: 1304 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.0758

Gnomad EAS AF: 0.0891

Gnomad SAS AF: 0.0843

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0986

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.129 AC: 32062 AN: 247736 Hom.: 3153 AF XY: 0.119 AC XY: 15911 AN XY: 134112

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.0747

Gnomad EAS exome AF: 0.0844

Gnomad SAS exome AF: 0.0764

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.0939

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.106 AC: 154611 AN: 1454140 Hom.: 9864 Cov.: 30 AF XY: 0.104 AC XY: 74862 AN XY: 723294

Gnomad4 AFR exome AF: 0.117

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.0748

Gnomad4 EAS exome AF: 0.0841

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.0995

Gnomad4 OTH exome AF: 0.104

GnomAD4 genome AF: 0.120 AC: 18278 AN: 152128 Hom.: 1312 Cov.: 32 AF XY: 0.125 AC XY: 9295 AN XY: 74372

Gnomad4 AFR AF: 0.120

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.0758

Gnomad4 EAS AF: 0.0897

Gnomad4 SAS AF: 0.0844

Gnomad4 FIN AF: 0.158

Gnomad4 NFE AF: 0.0986

Gnomad4 OTH AF: 0.115

Alfa AF: 0.0991 Hom.: 579

Bravo AF: 0.129

TwinsUK AF: 0.104 AC: 386

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.115 AC: 508

ESP6500EA AF: 0.0978 AC: 841

ExAC AF: 0.123 AC: 14905

Asia WGS AF: 0.115 AC: 399 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ART4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.20
Dann	Benign	0.76
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.0030
Sift	Benign	0.12	T
Sift4G	Uncertain	0.027	D
Vest4		0.035
MPC		0.0097
ClinPred		0.0049	T
GERP RS		-5.7
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3088190; hg19: chr12-14982352; COSMIC: COSV57451649;