19-1912163-C-T

Position:

• chr19-1912163-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138422.4(ADAT3):​c.116C>T​(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000916 in 1,419,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000092 (0 hom.)
• Consequence: ADAT3 NM_138422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.504

Genes affected

ADAT3 (HGNC:25151): (adenosine deaminase tRNA specific 3) This gene encodes a subunit of a tRNA-specific adenosine deaminase. This heterodimeric enzyme converts adenosine to inosine in the tRNA anticodon. A mutation in this gene causes a syndrome characterized by intellectual disability and strabismus. This gene shares its 5' exon with the overlapping gene, secretory carrier membrane protein 4 (Gene ID: 113178). [provided by RefSeq, Jul 2016]

SCAMP4 (HGNC:30385): (secretory carrier membrane protein 4) Secretory carrier membrane proteins (SCAMPs) are widely distributed integral membrane proteins implicated in membrane trafficking. Most SCAMPs (e.g., SCAMP1; MIM 606911) have N-terminal cytoplasmic NPF (arg-pro-phe) repeats, 4 central transmembrane regions, and a short C-terminal cytoplasmic tail. These SCAMPs likely have a role in endocytosis that is mediated by their NPF repeats. Other SCAMPs, such as SCAMP4, lack the NPF repeats and are therefore unlikely to function in endocytosis (summary by Fernandez-Chacon and Sudhof, 2000 [PubMed 11050114]).[supplied by OMIM, Feb 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053911567).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAT3	NM_138422.4	c.116C>T	p.Pro39Leu	missense_variant	2/2	ENST00000329478.4	NP_612431.2
SCAMP4	NM_079834.4	c.-41-2816C>T		intron_variant		ENST00000316097.13	NP_524558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAT3	ENST00000329478.4	c.116C>T	p.Pro39Leu	missense_variant	2/2	1	NM_138422.4	ENSP00000332448.2
SCAMP4	ENST00000316097.13	c.-41-2816C>T		intron_variant		1	NM_079834.4	ENSP00000316007.7

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000916 AC: 13 AN: 1419556 Hom.: 0 Cov.: 30 AF XY: 0.00000426 AC XY: 3 AN XY: 703440

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: 0.000111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000183

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 34

Bravo AF: 0.00000378

ExAC AF: 0.0000170 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.68C>T (p.P23L) alteration is located in exon 2 (coding exon 1) of the ADAT3 gene. This alteration results from a C to T substitution at nucleotide position 68, causing the proline (P) at amino acid position 23 to be replaced by a leucine (L). 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
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	13
DANN	Benign	0.80
DEOGEN2	Benign	0.064	.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.47	T
REVEL	Benign	0.099
Sift4G	Benign	0.13	T;T
Vest4		0.15
MVP		0.27
MPC		0.40
ClinPred		0.049	T
GERP RS		2.0
gMVP		0.25

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: rs764329582; hg19: chr19-1912162;