chr21-45537880-T-C

Variant names:

• chr21-45537880-T-C
• rs1051266
• NM_194255.4:c.80A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. 16/21 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 P:1 U:1 B:1 O:1
• Conservation: PhyloP100: 0.987
• Publications: 403 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.8591234E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194255.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A1	NM_194255.4	MANE Select	c.80A>G	p.His27Arg	missense	Exon 2 of 6	NP_919231.1
	SLC19A1	NM_001352512.2		c.80A>G	p.His27Arg	missense	Exon 2 of 6	NP_001339441.1
	SLC19A1	NM_001205206.4		c.80A>G	p.His27Arg	missense	Exon 2 of 6	NP_001192135.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.80A>G	p.His27Arg	missense	Exon 2 of 6	ENSP00000308895.4
	SLC19A1	ENST00000567670.5	TSL:1	c.80A>G	p.His27Arg	missense	Exon 2 of 6	ENSP00000457278.1
	SLC19A1	ENST00000380010.8	TSL:1	c.80A>G	p.His27Arg	missense	Exon 2 of 6	ENSP00000369347.4

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

GnomAD2 exomes AF: 0.550 AC: 125992 AN: 228958 AF XY: 0.556

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 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

African (AFR) AF: 0.373 AC: 12437 AN: 33362

American (AMR) AF: 0.563 AC: 24445 AN: 43400

Ashkenazi Jewish (ASJ) AF: 0.595 AC: 15429 AN: 25920

East Asian (EAS) AF: 0.451 AC: 17734 AN: 39308

South Asian (SAS) AF: 0.590 AC: 49837 AN: 84444

European-Finnish (FIN) AF: 0.549 AC: 26615 AN: 48462

Middle Eastern (MID) AF: 0.486 AC: 2792 AN: 5750

European-Non Finnish (NFE) AF: 0.568 AC: 628871 AN: 1107488

Other (OTH) AF: 0.550 AC: 32962 AN: 59960

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

African (AFR) AF: 0.390 AC: 16165 AN: 41444

American (AMR) AF: 0.569 AC: 8688 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2088 AN: 3470

East Asian (EAS) AF: 0.471 AC: 2436 AN: 5168

South Asian (SAS) AF: 0.594 AC: 2867 AN: 4824

European-Finnish (FIN) AF: 0.548 AC: 5794 AN: 10570

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.572 AC: 38836 AN: 67934

Other (OTH) AF: 0.509 AC: 1076 AN: 2114

Alfa AF: 0.555 Hom.: 98340

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

ClinVar submissions as Germline

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Gastrointestinal stromal tumor (1)
1	-	-	Lung cancer (1)
-	-	1	not provided (1)
-	-	-	methotrexate response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.000019	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.99
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.19
Sift	Benign	0.35	T
Sift4G	Benign	0.35	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
Mutation Taster		=100/0	polymorphism (auto)

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