chr19-1912430-G-T

Variant names:

• chr19-1912430-G-T
• rs200992550
• NM_138422.4:c.383G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138422.4(ADAT3):​c.383G>T​(p.Arg128Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00218 in 1,511,234 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (4 hom.)
• Consequence: ADAT3 NM_138422.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.191
• Publications: 2 publications found

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

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005703211).
• BP6: Variant 19-1912430-G-T is Benign according to our data. Variant chr19-1912430-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 450197.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138422.4. 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
	ADAT3	NM_138422.4	MANE Select	c.383G>T	p.Arg128Leu	missense	Exon 2 of 2	NP_612431.2	D6W601
	SCAMP4	NM_079834.4	MANE Select	c.-41-2549G>T		intron	N/A	NP_524558.1	Q969E2-1
	ADAT3	NM_001329533.2		c.335G>T	p.Arg112Leu	missense	Exon 2 of 2	NP_001316462.1	Q96EY9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAT3	ENST00000329478.4	TSL:1 MANE Select	c.383G>T	p.Arg128Leu	missense	Exon 2 of 2	ENSP00000332448.2	D6W601
	SCAMP4	ENST00000316097.13	TSL:1 MANE Select	c.-41-2549G>T		intron	N/A	ENSP00000316007.7	Q969E2-1
	SCAMP4	ENST00000414057.6	TSL:1	c.-125-5264G>T		intron	N/A	ENSP00000479672.1	A0A087WVT5

Frequencies

GnomAD3 genomes AF: 0.00226 AC: 344 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00235 AC: 248 AN: 105690 AF XY: 0.00237

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00492

Gnomad ASJ exome AF: 0.000835

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00202

Gnomad NFE exome AF: 0.00278

Gnomad OTH exome AF: 0.00307

GnomAD4 exome AF: 0.00217 AC: 2945 AN: 1359006 Hom.: 4 Cov.: 30 AF XY: 0.00217 AC XY: 1455 AN XY: 670410

African (AFR) AF: 0.000502 AC: 14 AN: 27878

American (AMR) AF: 0.00438 AC: 146 AN: 33320

Ashkenazi Jewish (ASJ) AF: 0.000702 AC: 17 AN: 24220

East Asian (EAS) AF: 0.00 AC: 0 AN: 32578

South Asian (SAS) AF: 0.000275 AC: 21 AN: 76498

European-Finnish (FIN) AF: 0.00196 AC: 66 AN: 33648

Middle Eastern (MID) AF: 0.000580 AC: 3 AN: 5172

European-Non Finnish (NFE) AF: 0.00239 AC: 2555 AN: 1069028

Other (OTH) AF: 0.00217 AC: 123 AN: 56664

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00232 AC XY: 173 AN XY: 74432

African (AFR) AF: 0.000409 AC: 17 AN: 41550

American (AMR) AF: 0.00660 AC: 101 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 67986

Other (OTH) AF: 0.00379 AC: 8 AN: 2110

Alfa AF: 0.00229 Hom.: 1

Bravo AF: 0.00227

ExAC AF: 0.000691 AC: 37

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	-	1	ADAT3-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.22
DANN	Benign	0.74
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.19
PrimateAI	Uncertain	0.72	T
REVEL	Benign	0.055
Sift4G	Benign	0.29	T
Vest4		0.16
MVP		0.27
MPC		0.49
ClinPred		0.0014	T
GERP RS		-8.5
gMVP		0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs200992550; hg19: chr19-1912429; COSMIC: COSV60190852; COSMIC: COSV60190852;