chr12-46197734-T-C

Position:

• chr12-46197734-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030674.4(SLC38A1):​c.1348A>G​(p.Thr450Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SLC38A1 NM_030674.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.105570525).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC38A1	NM_030674.4	c.1348A>G	p.Thr450Ala	missense_variant	16/17	ENST00000398637.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC38A1	ENST00000398637.10	c.1348A>G	p.Thr450Ala	missense_variant	16/17	1	NM_030674.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436022 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 714236

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: 9.07e-7

Gnomad4 OTH exome AF: 0.00

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 04, 2023

The c.1348A>G (p.T450A) alteration is located in exon 16 (coding exon 14) of the SLC38A1 gene. This alteration results from a A to G substitution at nucleotide position 1348, causing the threonine (T) at amino acid position 450 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	0.066
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	18
DANN	Benign	0.87
DEOGEN2	Benign	0.049	T;T;T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.57	.;.;.;T;.;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.11	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.97	L;L;L;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.90	N;N;N;N;N;.
REVEL	Benign	0.036
Sift	Benign	0.54	T;T;T;T;T;.
Sift4G	Benign	0.73	T;T;T;T;T;T
Polyphen		0.18	B;B;B;B;B;B
Vest4		0.18
MutPred		0.50		Gain of catalytic residue at T450 (P = 0.0071);Gain of catalytic residue at T450 (P = 0.0071);Gain of catalytic residue at T450 (P = 0.0071);Gain of catalytic residue at T450 (P = 0.0071);Gain of catalytic residue at T450 (P = 0.0071);Gain of catalytic residue at T450 (P = 0.0071);
MVP		0.082
MPC		0.59
ClinPred		0.051	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.043
gMVP		0.34

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: rs970234100; hg19: chr12-46591517;