12-46367275-T-C

Variant names:

• chr12-46367275-T-C
• rs145502537
• NM_018976.5:c.380A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018976.5(SLC38A2):​c.380A>G​(p.Asn127Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000112 in 1,596,652 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N127D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: SLC38A2 NM_018976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058236063).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC38A2	NM_018976.5	c.380A>G	p.Asn127Ser	missense_variant	Exon 5 of 16	ENST00000256689.10	NP_061849.2
SLC38A2	NM_001307936.2	c.80A>G	p.Asn27Ser	missense_variant	Exon 4 of 15		NP_001294865.1
SLC38A2	XM_047429019.1	c.80A>G	p.Asn27Ser	missense_variant	Exon 2 of 13		XP_047284975.1
SLC38A2	XM_047429020.1	c.380A>G	p.Asn127Ser	missense_variant	Exon 5 of 13		XP_047284976.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC38A2	ENST00000256689.10	c.380A>G	p.Asn127Ser	missense_variant	Exon 5 of 16	1	NM_018976.5	ENSP00000256689.5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 55 AN: 250740 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135552

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000441

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000949 AC: 137 AN: 1444340 Hom.: 0 Cov.: 27 AF XY: 0.0000972 AC XY: 70 AN XY: 719814

Gnomad4 AFR exome AF: 0.000788

Gnomad4 AMR exome AF: 0.000426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000278

Gnomad4 SAS exome AF: 0.000280

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000401

Gnomad4 OTH exome AF: 0.000201

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000825 Hom.: 0

Bravo AF: 0.000291

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.380A>G (p.N127S) alteration is located in exon 5 (coding exon 4) of the SLC38A2 gene. This alteration results from a A to G substitution at nucleotide position 380, causing the asparagine (N) at amino acid position 127 to be replaced by a serine (S). 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
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.016	T;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.16
Sift	Benign	0.56	T;.
Sift4G	Benign	0.60	T;T
Polyphen		1.0	D;P
Vest4		0.31
MVP		0.12
MPC		0.15
ClinPred		0.050	T
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.37

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: rs145502537; hg19: chr12-46761058;