15-84895102-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004213.5(SLC28A1):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00712 in 1,614,000 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0073 (51 hom.)
• Consequence: SLC28A1 NM_004213.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0220

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0055637658).
• BP6: Variant 15-84895102-G-A is Benign according to our data. Variant chr15-84895102-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2645652.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC28A1	NM_004213.5	c.440G>A	p.Arg147His	missense_variant	6/19	ENST00000394573.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC28A1	ENST00000394573.6	c.440G>A	p.Arg147His	missense_variant	6/19	1	NM_004213.5	P1
SLC28A1	ENST00000286749.3	c.440G>A	p.Arg147His	missense_variant	5/18	1		P1
SLC28A1	ENST00000338602.6	c.440G>A	p.Arg147His	missense_variant	6/7	1
SLC28A1	ENST00000538177.5	c.440G>A	p.Arg147His	missense_variant	5/15	2

Frequencies

GnomAD3 genomes AF: 0.00529 AC: 805 AN: 152172 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00740

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00726

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00540 AC: 1355 AN: 250818 Hom.: 1 AF XY: 0.00537 AC XY: 728 AN XY: 135664

Gnomad AFR exome AF: 0.000869

Gnomad AMR exome AF: 0.00451

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.0124

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00731 AC: 10684 AN: 1461710 Hom.: 51 Cov.: 35 AF XY: 0.00699 AC XY: 5083 AN XY: 727138

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00481

Gnomad4 ASJ exome AF: 0.00130

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.0111

Gnomad4 NFE exome AF: 0.00841

Gnomad4 OTH exome AF: 0.00699

GnomAD4 genome AF: 0.00528 AC: 804 AN: 152290 Hom.: 3 Cov.: 33 AF XY: 0.00536 AC XY: 399 AN XY: 74470

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00739

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.00726

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00656 Hom.: 8

Bravo AF: 0.00458

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00675 AC: 58

ExAC AF: 0.00517 AC: 628

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00692

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

SLC28A1: BP4, BS2 -

SLC28A1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 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	0.071
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	11
Dann	Benign	0.67
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.71	T;T;T;.
MetaRNN	Benign	0.0056	T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.5	M;.;M;M
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.094	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		1.0	D;B;B;B
Vest4		0.063
MVP		0.43
MPC		0.094
ClinPred		0.0059	T
GERP RS		0.34
Varity_R		0.033
gMVP		0.12

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: rs116707209; hg19: chr15-85438333; COSMIC: COSV99075104;