chr16-75608251-T-C

Position:

• chr16-75608251-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001324445.2(ADAT1):​c.1262A>G​(p.Lys421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ADAT1 NM_001324445.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

Genes affected

ADAT1 (HGNC:228): (adenosine deaminase tRNA specific 1) This gene is a member of the ADAR (adenosine deaminase acting on RNA) family. Using site-specific adenosine modification, proteins encoded by these genes participate in the pre-mRNA editing of nuclear transcripts. The protein encoded by this gene, tRNA-specific adenosine deaminase 1, is responsible for the deamination of adenosine 37 to inosine in eukaryotic tRNA. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jul 2010]

ENSG00000259992 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2861061).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAT1	NM_001324445.2	c.1262A>G	p.Lys421Arg	missense_variant	8/10	ENST00000564657.2	NP_001311374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAT1	ENST00000564657.2	c.1262A>G	p.Lys421Arg	missense_variant	8/10	2	NM_001324445.2	ENSP00000457501.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461774 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727192

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

May 11, 2022

The c.1262A>G (p.K421R) alteration is located in exon 9 (coding exon 7) of the ADAT1 gene. This alteration results from a A to G substitution at nucleotide position 1262, causing the lysine (K) at amino acid position 421 to be replaced by an arginine (R). 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	Benign	0.069
BayesDel_addAF	Benign	-0.0025	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.29	T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.28
Sift	Benign	0.38	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.12	.;B
Vest4		0.29
MutPred		0.71		.;Loss of methylation at K421 (P = 0.0335);
MVP		0.82
MPC		0.012
ClinPred		0.21	T
GERP RS		3.1
Varity_R		0.049
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2081422909; hg19: chr16-75642149;