10-121743745-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001001976.3(ATE1):​c.1492G>T​(p.Val498Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V498I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

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>T	p.Val498Phe	missense	Exon 12 of 12	NP_001001976.1	O95260-1
	ATE1	NM_001439361.1		c.1672G>T	p.Val558Phe	missense	Exon 13 of 13	NP_001426290.1
	ATE1	NM_001437419.1		c.1621G>T	p.Val541Phe	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>T	p.Val498Phe	missense	Exon 12 of 12	ENSP00000224652.6	O95260-1
	ATE1	ENST00000369043.8	TSL:1	c.1492G>T	p.Val498Phe	missense	Exon 12 of 12	ENSP00000358039.3	O95260-2
	ATE1	ENST00000423243.7	TSL:1	n.*1209G>T		non_coding_transcript_exon	Exon 10 of 10	ENSP00000397787.2	H0Y5C2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 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: 0.0000252 AC: 1 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

GnomAD4 genome Cov.: 32

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	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.21	T
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.31		Loss of disorder (P = 0.2081)
MVP		0.54
MPC		0.48
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.33
gMVP		0.82
Mutation Taster		=45/55	disease causing

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;