rs1051266

chr21-45537880-T-Cchr21-45537880-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The NM_194255.4(SLC19A1):c.80A>G(p.His27Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.556 in 1,600,100 control chromosomes in the GnomAD database, including 249,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20951 hom., cov: 32)
  • Exomes 𝑓: 0.56 (228513 hom.)
• Consequence: SLC19A1 NM_194255.4 missense
• Clinical Significance: drug response reviewed by expert panel U:1 B:1 O:1
• Conservation: PhyloP100: 0.987

Genes affected

SLC19A1 (HGNC:10937): (solute carrier family 19 member 1) The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8591234E-5).
• BP6: Variant 21-45537880-T-C is Benign according to our data. Variant chr21-45537880-T-C is described in ClinVar as [drug_response]. Clinvar id is 157588.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {drug_response=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A1	NM_194255.4	c.80A>G	p.His27Arg	missense_variant	2/6	ENST00000311124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A1	ENST00000311124.9	c.80A>G	p.His27Arg	missense_variant	2/6	1	NM_194255.4	A2

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78652 AN: 151888 Hom.: 20924 Cov.: 32

Gnomad AFR AF: 0.390

Gnomad AMI AF: 0.686

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.594

Gnomad FIN AF: 0.548

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.503

GnomAD3 exomes AF: 0.550 AC: 125992 AN: 228958 Hom.: 34859 AF XY: 0.556 AC XY: 69279 AN XY: 124500

Gnomad AFR exome AF: 0.377

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.601

Gnomad EAS exome AF: 0.471

Gnomad SAS exome AF: 0.592

Gnomad FIN exome AF: 0.551

Gnomad NFE exome AF: 0.568

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.560 AC: 811122 AN: 1448094 Hom.: 228513 Cov.: 46 AF XY: 0.562 AC XY: 404045 AN XY: 719546

Gnomad4 AFR exome AF: 0.373

Gnomad4 AMR exome AF: 0.563

Gnomad4 ASJ exome AF: 0.595

Gnomad4 EAS exome AF: 0.451

Gnomad4 SAS exome AF: 0.590

Gnomad4 FIN exome AF: 0.549

Gnomad4 NFE exome AF: 0.568

Gnomad4 OTH exome AF: 0.550

GnomAD4 genome AF: 0.518 AC: 78718 AN: 152006 Hom.: 20951 Cov.: 32 AF XY: 0.519 AC XY: 38536 AN XY: 74280

Gnomad4 AFR AF: 0.390

Gnomad4 AMR AF: 0.569

Gnomad4 ASJ AF: 0.602

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.548

Gnomad4 NFE AF: 0.572

Gnomad4 OTH AF: 0.509

Alfa AF: 0.561 Hom.: 43663

Bravo AF: 0.512

TwinsUK AF: 0.559 AC: 2073

ALSPAC AF: 0.573 AC: 2208

ESP6500AA AF: 0.391 AC: 1717

ESP6500EA AF: 0.569 AC: 4894

ExAC AF: 0.533 AC: 64099

Asia WGS AF: 0.534 AC: 1854 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

Department of Pharmacy and Biotechnology, University of Bologna

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

methotrexate response - Efficacy Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	6.1
Dann	Benign	0.50
DEOGEN2	Benign	0.13	T;T;.;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.12	T;T;T;T;T;T
MetaRNN	Benign	0.000019	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.61	N;N;N;N;N;N
Sift	Benign	0.35	T;T;T;T;T;T
Sift4G	Benign	0.35	T;T;T;.;.;.
Polyphen		0.0	.;B;.;.;.;.
Vest4		0.0080
MPC		0.11
ClinPred		0.0042	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.021
gMVP		0.34

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: rs1051266; hg19: chr21-46957794; COSMIC: COSV60752997; COSMIC: COSV60752997;