rs745771967

Variant names:

• chr15-84890532-C-T
• rs745771967
• NM_004213.5:c.275C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004213.5(SLC28A1):​c.275C>T​(p.Thr92Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,455,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SLC28A1 NM_004213.5 missense, splice_region
• Scores: Splicing: ADA: 0.4799
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.53
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42111862).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC28A1	NM_004213.5	c.275C>T	p.Thr92Ile	missense_variant, splice_region_variant	Exon 5 of 19	ENST00000394573.6	NP_004204.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC28A1	ENST00000394573.6	c.275C>T	p.Thr92Ile	missense_variant, splice_region_variant	Exon 5 of 19	1	NM_004213.5	ENSP00000378074.1
SLC28A1	ENST00000286749.3	c.275C>T	p.Thr92Ile	missense_variant, splice_region_variant	Exon 4 of 18	1		ENSP00000286749.3
SLC28A1	ENST00000338602.6	c.275C>T	p.Thr92Ile	missense_variant, splice_region_variant	Exon 5 of 7	1		ENSP00000341629.2
SLC28A1	ENST00000538177.5	c.275C>T	p.Thr92Ile	missense_variant, splice_region_variant	Exon 4 of 15	2		ENSP00000443752.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000123 AC: 3 AN: 244404 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1455324 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 723952

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5116

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109052

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 18, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.275C>T (p.T92I) alteration is located in exon 5 (coding exon 3) of the SLC28A1 gene. This alteration results from a C to T substitution at nucleotide position 275, causing the threonine (T) at amino acid position 92 to be replaced by an isoleucine (I). 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	0.11
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0053	.;T;T;T
Eigen	Benign	0.084
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.69	T;T;T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.42	T;T;T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M;.;M;M
PhyloP100		3.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.51
Sift	Benign	0.48	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		1.0	D;P;B;B
Vest4		0.68
MutPred		0.36		Loss of catalytic residue at T92 (P = 0.152);Loss of catalytic residue at T92 (P = 0.152);Loss of catalytic residue at T92 (P = 0.152);Loss of catalytic residue at T92 (P = 0.152);
MVP		0.90
MPC		0.22
ClinPred		0.33	T
GERP RS		4.3
Varity_R		0.096
gMVP		0.26
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.48
dbscSNV1_RF	Benign	0.43
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

Other links and lift over

dbSNP: rs745771967; hg19: chr15-85433763;