19-1912109-C-T

Variant names:

• chr19-1912109-C-T
• rs538664300
• NM_138422.4:c.62C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_138422.4(ADAT3):​c.62C>T​(p.Pro21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000509 in 1,521,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P21R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: ADAT3 NM_138422.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0062256157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAT3	NM_138422.4	c.62C>T	p.Pro21Leu	missense_variant	Exon 2 of 2	ENST00000329478.4	NP_612431.2
SCAMP4	NM_079834.4	c.-41-2870C>T		intron_variant	Intron 1 of 6	ENST00000316097.13	NP_524558.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAT3	ENST00000329478.4	c.62C>T	p.Pro21Leu	missense_variant	Exon 2 of 2	1	NM_138422.4	ENSP00000332448.2
SCAMP4	ENST00000316097.13	c.-41-2870C>T		intron_variant	Intron 1 of 6	1	NM_079834.4	ENSP00000316007.7

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152268 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000558

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000339 AC: 41 AN: 120892 AF XY: 0.000374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000487

Gnomad ASJ exome AF: 0.000627

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000723

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000532 AC: 728 AN: 1368664 Hom.: 0 Cov.: 30 AF XY: 0.000485 AC XY: 327 AN XY: 674794

African (AFR) AF: 0.0000333 AC: 1 AN: 30008

American (AMR) AF: 0.0000929 AC: 3 AN: 32280

Ashkenazi Jewish (ASJ) AF: 0.000895 AC: 21 AN: 23462

East Asian (EAS) AF: 0.00 AC: 0 AN: 35214

South Asian (SAS) AF: 0.0000264 AC: 2 AN: 75838

European-Finnish (FIN) AF: 0.0000264 AC: 1 AN: 37892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.000640 AC: 686 AN: 1071486

Other (OTH) AF: 0.000246 AC: 14 AN: 57012

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152386 Hom.: 0 Cov.: 34 AF XY: 0.000255 AC XY: 19 AN XY: 74518

African (AFR) AF: 0.0000481 AC: 2 AN: 41600

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000558 AC: 38 AN: 68044

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000295

ExAC AF: 0.000349 AC: 39

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.26
DANN	Benign	0.72
DEOGEN2	Benign	0.013	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0062	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.0062	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.092
Sift	Benign	0.66	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.098
MVP		0.11
MPC		0.40
ClinPred		0.0052	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.17
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs538664300; hg19: chr19-1912108;