chr19-1912069-TGTCTCCCACAGTCG-T

Position:

• chr19-1912069-TGTCTCCCACAGTCG-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001329533.2(ADAT3):​c.-15-10_-12delTCTCCCACAGTCGG variant causes a splice acceptor, splice region, 5 prime UTR, intron change. The variant allele was found at a frequency of 0.00019 in 1,440,024 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ADAT3 NM_001329533.2 splice_acceptor, splice_region, 5_prime_UTR, intron
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.44

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 1.0037593984962405 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.6, offset of -40, new splice context is: tctcccccagccgcccgcAGccg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1912069-TGTCTCCCACAGTCG-T is Pathogenic according to our data. Variant chr19-1912069-TGTCTCCCACAGTCG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1331555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAT3	NM_138422.4	c.24_37delTCTCCCACAGTCGG	p.Pro10fs	frameshift_variant	2/2	ENST00000329478.4	NP_612431.2
SCAMP4	NM_079834.4	c.-41-2908_-41-2895delTCTCCCACAGTCGG		intron_variant		ENST00000316097.13	NP_524558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAT3	ENST00000329478.4	c.24_37delTCTCCCACAGTCGG	p.Pro10fs	frameshift_variant	2/2	1	NM_138422.4	ENSP00000332448.2
SCAMP4	ENST00000316097.13	c.-41-2908_-41-2895delTCTCCCACAGTCGG		intron_variant		1	NM_079834.4	ENSP00000316007.7

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000596 AC: 3 AN: 50308 Hom.: 0 AF XY: 0.000109 AC XY: 3 AN XY: 27550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000155

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000202 AC: 260 AN: 1287784 Hom.: 0 AF XY: 0.000196 AC XY: 123 AN XY: 627974

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: 0.000249

Gnomad4 OTH exome AF: 0.0000561

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152240 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74384

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000872 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Nov 03, 2020

PVS1, PM2 -

Intellectual disability-strabismus syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs752360082; hg19: chr19-1912068;