12-46198662-A-G

Position:

• chr12-46198662-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030674.4(SLC38A1):​c.1085T>C​(p.Val362Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC38A1 NM_030674.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28415307).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC38A1	NM_030674.4	c.1085T>C	p.Val362Ala	missense_variant	14/17	ENST00000398637.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC38A1	ENST00000398637.10	c.1085T>C	p.Val362Ala	missense_variant	14/17	1	NM_030674.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Feb 28, 2024

The c.1085T>C (p.V362A) alteration is located in exon 14 (coding exon 12) of the SLC38A1 gene. This alteration results from a T to C substitution at nucleotide position 1085, causing the valine (V) at amino acid position 362 to be replaced by an alanine (A). 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	0.12
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.089	T;T;T;T;.;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.67	D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.28	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L;.;.
MutationTaster	Benign	0.93	N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N;N;N;N;N;.
REVEL	Benign	0.15
Sift	Benign	0.069	T;T;T;T;D;.
Sift4G	Benign	0.18	T;T;T;T;T;T
Polyphen		0.10	B;B;B;B;B;B
Vest4		0.57
MutPred		0.57		Gain of catalytic residue at L366 (P = 0);Gain of catalytic residue at L366 (P = 0);Gain of catalytic residue at L366 (P = 0);Gain of catalytic residue at L366 (P = 0);Gain of catalytic residue at L366 (P = 0);Gain of catalytic residue at L366 (P = 0);
MVP		0.082
MPC		0.78
ClinPred		0.48	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.77

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

Publications

LitVar

Other links and lift over

dbSNP: rs1939498933; hg19: chr12-46592445;