12-46207591-T-G

Position:

• chr12-46207591-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_030674.4(SLC38A1):​c.419A>C​(p.Gln140Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 2.96

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC38A1	NM_030674.4	c.419A>C	p.Gln140Pro	missense_variant	7/17	ENST00000398637.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC38A1	ENST00000398637.10	c.419A>C	p.Gln140Pro	missense_variant	7/17	1	NM_030674.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Aug 21, 2023

The c.419A>C (p.Q140P) alteration is located in exon 7 (coding exon 5) of the SLC38A1 gene. This alteration results from a A to C substitution at nucleotide position 419, causing the glutamine (Q) at amino acid position 140 to be replaced by a proline (P). 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	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T;T;.;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	.;.;.;D;.;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.90	L;L;L;L;.;.
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.4	N;N;N;N;N;.
REVEL	Benign	0.27
Sift	Benign	0.093	T;T;T;T;D;.
Sift4G	Uncertain	0.039	D;D;D;D;D;D
Polyphen		0.92	P;P;P;P;P;P
Vest4		0.87
MutPred		0.60		Gain of catalytic residue at T145 (P = 0);Gain of catalytic residue at T145 (P = 0);Gain of catalytic residue at T145 (P = 0);Gain of catalytic residue at T145 (P = 0);Gain of catalytic residue at T145 (P = 0);Gain of catalytic residue at T145 (P = 0);
MVP		0.60
MPC		1.5
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.58
gMVP		0.89

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-46601374;