10-121743745-C-T

Variant names:

• chr10-121743745-C-T
• rs958173314
• NM_001001976.3:c.1492G>A

Variant summary

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

The NM_001001976.3(ATE1):​c.1492G>A​(p.Val498Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V498F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ATE1 NM_001001976.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

ATE1 (HGNC:782): (arginyltransferase 1) This gene encodes an arginyltransferase, an enzyme that is involved in posttranslational conjugation of arginine to N-terminal aspartate or glutamate residues. Conjugation of arginine to the N-terminal aspartate or glutamate targets proteins for ubiquitin-dependent degradation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

ATE1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

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=0.1971049).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001976.3. 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
	ATE1	NM_001001976.3	MANE Select	c.1492G>A	p.Val498Ile	missense	Exon 12 of 12	NP_001001976.1	O95260-1
	ATE1	NM_001439361.1		c.1672G>A	p.Val558Ile	missense	Exon 13 of 13	NP_001426290.1
	ATE1	NM_001437419.1		c.1621G>A	p.Val541Ile	missense	Exon 13 of 13	NP_001424348.1	A0A8I5KZ24

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATE1	ENST00000224652.12	TSL:1 MANE Select	c.1492G>A	p.Val498Ile	missense	Exon 12 of 12	ENSP00000224652.6	O95260-1
	ATE1	ENST00000369043.8	TSL:1	c.1492G>A	p.Val498Ile	missense	Exon 12 of 12	ENSP00000358039.3	O95260-2
	ATE1	ENST00000423243.7	TSL:1	n.*1209G>A		non_coding_transcript_exon	Exon 10 of 10	ENSP00000397787.2	H0Y5C2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

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	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.083	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.96	T
PhyloP100		3.6
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.078
Sift	Benign	0.36	T
Sift4G	Benign	0.57	T
Polyphen		0.73	P
Vest4		0.14
MutPred		0.26		Gain of phosphorylation at Y501 (P = 0.1587)
MVP		0.21
MPC		0.17
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.045
gMVP		0.35
Mutation Taster		=88/12	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: rs958173314; hg19: chr10-123503260;