19-1912166-C-T

Position:

• chr19-1912166-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138422.4(ADAT3):​c.119C>T​(p.Ala40Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000223 in 1,572,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: ADAT3 NM_138422.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.660

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]

SCAMP4 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059817433).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAT3	NM_138422.4	c.119C>T	p.Ala40Val	missense_variant	2/2	ENST00000329478.4	NP_612431.2
SCAMP4	NM_079834.4	c.-41-2813C>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.119C>T	p.Ala40Val	missense_variant	2/2	1	NM_138422.4	ENSP00000332448.2
SCAMP4	ENST00000316097.13	c.-41-2813C>T		intron_variant		1	NM_079834.4	ENSP00000316007.7

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152266 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000351 AC: 61 AN: 173970 Hom.: 0 AF XY: 0.000377 AC XY: 36 AN XY: 95538

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000732

Gnomad SAS exome AF: 0.000568

Gnomad FIN exome AF: 0.0000867

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.000855

GnomAD4 exome AF: 0.000226 AC: 321 AN: 1419774 Hom.: 2 Cov.: 30 AF XY: 0.000236 AC XY: 166 AN XY: 703600

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.000591

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000211

Gnomad4 SAS exome AF: 0.000431

Gnomad4 FIN exome AF: 0.0000461

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.000288

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152384 Hom.: 0 Cov.: 34 AF XY: 0.000215 AC XY: 16 AN XY: 74518

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000262 Hom.: 0

Bravo AF: 0.000257

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000340 AC: 40

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Jul 09, 2024

The c.71C>T (p.A24V) 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 71, causing the alanine (A) at amino acid position 24 to be replaced by a valine (V). 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	-0.51	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.77
DANN	Benign	0.84
DEOGEN2	Benign	0.011	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0060	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.44	T
REVEL	Benign	0.033
Sift4G	Benign	0.31	T;T
Vest4		0.063
MVP		0.24
MPC		0.39
ClinPred		0.0037	T
GERP RS		-7.1
gMVP		0.18

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: rs201103825; hg19: chr19-1912165;