12-46239686-T-C

Position:

• chr12-46239686-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030674.4(SLC38A1):​c.115A>G​(p.Ile39Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,420 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC38A1 NM_030674.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.72

Genes affected

SLC38A1 (HGNC:13447): (solute carrier family 38 member 1) Amino acid transporters play essential roles in the uptake of nutrients, production of energy, chemical metabolism, detoxification, and neurotransmitter cycling. SLC38A1 is an important transporter of glutamine, an intermediate in the detoxification of ammonia and the production of urea. Glutamine serves as a precursor for the synaptic transmitter, glutamate (Gu et al., 2001 [PubMed 11325958]).[supplied by OMIM, Mar 2008]

SLC38A1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC38A1	NM_030674.4	c.115A>G	p.Ile39Val	missense_variant	3/17	ENST00000398637.10	NP_109599.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC38A1	ENST00000398637.10	c.115A>G	p.Ile39Val	missense_variant	3/17	1	NM_030674.4	ENSP00000381634.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461420 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727024

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: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 24, 2024

The c.115A>G (p.I39V) alteration is located in exon 3 (coding exon 1) of the SLC38A1 gene. This alteration results from a A to G substitution at nucleotide position 115, causing the isoleucine (I) at amino acid position 39 to be replaced by a valine (V). 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	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.060	T;T;T;T;.;.;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.028
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	.;.;.;T;.;T;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;N;N;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.17	N;N;N;N;N;.;N
REVEL	Benign	0.099
Sift	Benign	0.56	T;T;T;T;T;.;T
Sift4G	Benign	0.39	T;T;T;T;T;T;.
Polyphen		0.0060	B;B;B;B;B;B;.
Vest4		0.38
MutPred		0.26		Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);Gain of catalytic residue at K42 (P = 0.011);
MVP		0.16
MPC		0.47
ClinPred		0.37	T
GERP RS		4.9
Varity_R		0.072
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1011669499; hg19: chr12-46633469;