15-84904203-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004213.5(SLC28A1):c.568G>T(p.Ala190Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,092 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 33)
  • Exomes 𝑓: 0.013 (136 hom.)
• Consequence: SLC28A1 NM_004213.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.60

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058966577).
• BP6: Variant 15-84904203-G-T is Benign according to our data. Variant chr15-84904203-G-T is described in ClinVar as [Benign]. Clinvar id is 3041811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0128 (1943/152312) while in subpopulation AFR AF= 0.0166 (689/41554). AF 95% confidence interval is 0.0156. There are 19 homozygotes in gnomad4. There are 849 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC28A1	NM_004213.5	c.568G>T	p.Ala190Ser	missense_variant	7/19	ENST00000394573.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC28A1	ENST00000394573.6	c.568G>T	p.Ala190Ser	missense_variant	7/19	1	NM_004213.5	P1
SLC28A1	ENST00000286749.3	c.568G>T	p.Ala190Ser	missense_variant	6/18	1		P1
SLC28A1	ENST00000538177.5	c.568G>T	p.Ala190Ser	missense_variant	6/15	2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1940 AN: 152194 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00971 AC: 2440 AN: 251392 Hom.: 17 AF XY: 0.00918 AC XY: 1247 AN XY: 135870

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.00882

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.000652

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00107

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0114

GnomAD4 exome AF: 0.0128 AC: 18746 AN: 1461780 Hom.: 136 Cov.: 34 AF XY: 0.0123 AC XY: 8960 AN XY: 727192

Gnomad4 AFR exome AF: 0.0173

Gnomad4 AMR exome AF: 0.00955

Gnomad4 ASJ exome AF: 0.0103

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.00116

Gnomad4 FIN exome AF: 0.00156

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0130

GnomAD4 genome AF: 0.0128 AC: 1943 AN: 152312 Hom.: 19 Cov.: 33 AF XY: 0.0114 AC XY: 849 AN XY: 74498

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0104

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0129 Hom.: 30

Bravo AF: 0.0146

TwinsUK AF: 0.0165 AC: 61

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.0138 AC: 61

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.00923 AC: 1121

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0131

EpiControl AF: 0.0154

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLC28A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.0010
Dann	Benign	0.66
DEOGEN2	Benign	0.014	T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.19	T;T;.
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.99	N;N;N
REVEL	Benign	0.014
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.012	B;B;B
Vest4		0.12
MVP		0.18
MPC		0.071
ClinPred		0.0077	T
GERP RS		-8.8
Varity_R		0.071
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs45523532; hg19: chr15-85447434; COSMIC: COSV99075105;