chr12-46362364-T-A

Variant names:

• chr12-46362364-T-A
• rs773814719
• NM_018976.5:c.1342A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018976.5(SLC38A2):​c.1342A>T​(p.Met448Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. M448V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC38A2 NM_018976.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.61
• Publications: 0 publications found

Genes affected

SLC38A2 (HGNC:13448): (solute carrier family 38 member 2) Enables neutral amino acid:sodium symporter activity. Involved in several processes, including amino acid transport; cellular response to arsenite(3-); and positive regulation of RNA splicing. Located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39472383).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018976.5. 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
	SLC38A2	NM_018976.5	MANE Select	c.1342A>T	p.Met448Leu	missense	Exon 15 of 16	NP_061849.2
	SLC38A2	NM_001307936.2		c.1042A>T	p.Met348Leu	missense	Exon 14 of 15	NP_001294865.1	Q96QD8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC38A2	ENST00000256689.10	TSL:1 MANE Select	c.1342A>T	p.Met448Leu	missense	Exon 15 of 16	ENSP00000256689.5	Q96QD8-1
	SLC38A2	ENST00000612232.1	TSL:1	c.1042A>T	p.Met348Leu	missense	Exon 12 of 13	ENSP00000482873.1	Q96QD8-2
	SLC38A2	ENST00000901221.1		c.1342A>T	p.Met448Leu	missense	Exon 14 of 15	ENSP00000571280.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725978

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44378

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 85844

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111018

Other (OTH) AF: 0.00 AC: 0 AN: 60268

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Benign	0.027	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.92	P
Vest4		0.58
MutPred		0.70		Gain of glycosylation at S444 (P = 0.1752)
MVP		0.33
MPC		0.23
ClinPred		0.94	D
GERP RS		6.1
Varity_R		0.31
gMVP		0.72
Mutation Taster		=36/64	disease causing

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: rs773814719; hg19: chr12-46756147;