15-84888842-C-G

Variant summary

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

The NM_004213.5(SLC28A1):c.167C>G(p.Pro56Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,256 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P56L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC28A1 NM_004213.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0900

Genes affected

SLC28A1 (HGNC:11001): (solute carrier family 28 member 1) Enables azole transmembrane transporter activity; cytidine transmembrane transporter activity; and uridine transmembrane transporter activity. Involved in azole transmembrane transport; nucleoside transport; and pyrimidine-containing compound transmembrane transport. Located in cytosol; nuclear speck; 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=0.06376156).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC28A1	NM_004213.5	c.167C>G	p.Pro56Arg	missense_variant	4/19	ENST00000394573.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC28A1	ENST00000394573.6	c.167C>G	p.Pro56Arg	missense_variant	4/19	1	NM_004213.5	P1
SLC28A1	ENST00000286749.3	c.167C>G	p.Pro56Arg	missense_variant	3/18	1		P1
SLC28A1	ENST00000338602.6	c.167C>G	p.Pro56Arg	missense_variant	4/7	1
SLC28A1	ENST00000538177.5	c.167C>G	p.Pro56Arg	missense_variant	3/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400256 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690840

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: 9.26e-7

Gnomad4 OTH exome AF: 0.0000172

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

Jan 02, 2024

The c.167C>G (p.P56R) alteration is located in exon 4 (coding exon 2) of the SLC28A1 gene. This alteration results from a C to G substitution at nucleotide position 167, causing the proline (P) at amino acid position 56 to be replaced by an arginine (R). 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	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	3.4
Dann	Benign	0.29
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.57	T;T;T;.
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.064	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.88	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.52	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.14	B;B;B;B
Vest4		0.091
MutPred		0.24		Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);Gain of MoRF binding (P = 0.0056);
MVP		0.22
MPC		0.082
ClinPred		0.069	T
GERP RS		0.13
Varity_R		0.025
gMVP		0.14

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: rs1196209657; hg19: chr15-85432073;