NM_001001976.3:c.976G>A

Variant names:

• chr10-121841263-C-T
• rs546621784
• NM_001001976.3:c.976G>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.976G>A​(p.Ala326Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000379 in 1,320,424 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: ATE1 NM_001001976.3 missense, splice_region
• Scores: Splicing: ADA: 0.001600
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72
• Publications: 2 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=0.19693434).

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.976G>A	p.Ala326Thr	missense splice_region	Exon 9 of 12	NP_001001976.1	O95260-1
	ATE1	NM_001439361.1		c.1156G>A	p.Ala386Thr	missense splice_region	Exon 10 of 13	NP_001426290.1
	ATE1	NM_001437419.1		c.1105G>A	p.Ala369Thr	missense splice_region	Exon 10 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.976G>A	p.Ala326Thr	missense splice_region	Exon 9 of 12	ENSP00000224652.6	O95260-1
	ATE1	ENST00000369043.8	TSL:1	c.976G>A	p.Ala326Thr	missense splice_region	Exon 9 of 12	ENSP00000358039.3	O95260-2
	ATE1	ENST00000423243.7	TSL:1	n.*693G>A		splice_region non_coding_transcript_exon	Exon 7 of 10	ENSP00000397787.2	H0Y5C2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000510 AC: 1 AN: 196134 AF XY: 0.00000931

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000473

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000379 AC: 5 AN: 1320424 Hom.: 0 Cov.: 31 AF XY: 0.00000308 AC XY: 2 AN XY: 650114

African (AFR) AF: 0.00 AC: 0 AN: 29596

American (AMR) AF: 0.00 AC: 0 AN: 32256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21866

East Asian (EAS) AF: 0.00 AC: 0 AN: 36178

South Asian (SAS) AF: 0.00 AC: 0 AN: 57196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5192

European-Non Finnish (NFE) AF: 0.00000482 AC: 5 AN: 1037108

Other (OTH) AF: 0.00 AC: 0 AN: 53592

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	0.15
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Benign	0.72
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		2.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.027
Sift	Benign	0.42	T
Sift4G	Benign	0.59	T
Polyphen		0.0070	B
Vest4		0.28
MVP		0.18
MPC		0.14
ClinPred		0.18	T
GERP RS		3.8
PromoterAI		-0.036	Neutral
Varity_R		0.060
gMVP		0.44
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0016
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.15		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: rs546621784; hg19: chr10-123600778;