NM_004213.5:c.391C>T

Variant names:

• chr15-84895053-C-T
• rs764328328
• NM_004213.5:c.391C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004213.5(SLC28A1):​c.391C>T​(p.Leu131Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000435 in 1,611,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SLC28A1 NM_004213.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0600
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016629696).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC28A1	NM_004213.5	c.391C>T	p.Leu131Phe	missense_variant	Exon 6 of 19	ENST00000394573.6	NP_004204.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC28A1	ENST00000394573.6	c.391C>T	p.Leu131Phe	missense_variant	Exon 6 of 19	1	NM_004213.5	ENSP00000378074.1
SLC28A1	ENST00000286749.3	c.391C>T	p.Leu131Phe	missense_variant	Exon 5 of 18	1		ENSP00000286749.3
SLC28A1	ENST00000338602.6	c.391C>T	p.Leu131Phe	missense_variant	Exon 6 of 7	1		ENSP00000341629.2
SLC28A1	ENST00000538177.5	c.391C>T	p.Leu131Phe	missense_variant	Exon 5 of 15	2		ENSP00000443752.1

Frequencies

GnomAD3 genomes AF: 0.0000201 AC: 3 AN: 149388 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000584

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251430 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461646 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727138

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111842

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome AF: 0.0000201 AC: 3 AN: 149388 Hom.: 0 Cov.: 33 AF XY: 0.0000274 AC XY: 2 AN XY: 72868

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40392

American (AMR) AF: 0.00 AC: 0 AN: 14978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3408

East Asian (EAS) AF: 0.000584 AC: 3 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10368

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67098

Other (OTH) AF: 0.00 AC: 0 AN: 2034

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000005), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391C>T (p.L131F) alteration is located in exon 6 (coding exon 4) of the SLC28A1 gene. This alteration results from a C to T substitution at nucleotide position 391, causing the leucine (L) at amino acid position 131 to be replaced by a phenylalanine (F). 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	0.071
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.4
DANN	Benign	0.69
DEOGEN2	Benign	0.0052	.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.58	T;T;T;.
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.017	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.6	L;.;L;L
PhyloP100		0.060
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.25	T;T;T;T
Sift4G	Benign	0.074	T;T;T;T
Polyphen		1.0	D;B;B;B
Vest4		0.097
MutPred		0.26		Gain of MoRF binding (P = 0.1017);Gain of MoRF binding (P = 0.1017);Gain of MoRF binding (P = 0.1017);Gain of MoRF binding (P = 0.1017);
MVP		0.21
MPC		0.084
ClinPred		0.022	T
GERP RS		-3.6
Varity_R		0.037
gMVP		0.096

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

Other links and lift over

dbSNP: rs764328328; hg19: chr15-85438284;