chr10-121743784-A-G

Position:

• chr10-121743784-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001001976.3(ATE1):​c.1453T>C​(p.Tyr485His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar 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: 7.34

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATE1	NM_001001976.3	c.1453T>C	p.Tyr485His	missense_variant	12/12	ENST00000224652.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATE1	ENST00000224652.12	c.1453T>C	p.Tyr485His	missense_variant	12/12	1	NM_001001976.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.1453T>C (p.Y485H) alteration is located in exon 12 (coding exon 12) of the ATE1 gene. This alteration results from a T to C substitution at nucleotide position 1453, causing the tyrosine (Y) at amino acid position 485 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;T;T;T;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.55	D;D;D;D;D
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;D;D
Vest4		0.58
MutPred		0.50		Loss of phosphorylation at Y485 (P = 0.0183);.;.;.;Loss of phosphorylation at Y485 (P = 0.0183);
MVP		0.43
MPC		0.72
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.74
gMVP		0.74

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

Publications

LitVar

Other links and lift over

dbSNP: rs746264073; hg19: chr10-123503299;