21-45531642-A-G

Variant names:

• chr21-45531642-A-G
• rs12659
• NM_194255.4:c.696T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_194255.4(SLC19A1):​c.696T>C​(p.Pro232Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 1,611,988 control chromosomes in the GnomAD database, including 269,684 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25021 hom., cov: 35)
  • Exomes 𝑓: 0.58 (244663 hom.)
• Consequence: SLC19A1 NM_194255.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.56
• Publications: 51 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 21-45531642-A-G is Benign according to our data. Variant chr21-45531642-A-G is described in ClinVar as Benign. ClinVar VariationId is 1601263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.622 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.696T>C	p.Pro232Pro	synonymous	Exon 3 of 6	NP_919231.1
	SLC19A1	NM_001352512.2		c.696T>C	p.Pro232Pro	synonymous	Exon 3 of 6	NP_001339441.1
	SLC19A1	NM_001205207.3		c.576T>C	p.Pro192Pro	synonymous	Exon 2 of 5	NP_001192136.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.696T>C	p.Pro232Pro	synonymous	Exon 3 of 6	ENSP00000308895.4
	SLC19A1	ENST00000567670.5	TSL:1	c.696T>C	p.Pro232Pro	synonymous	Exon 3 of 6	ENSP00000457278.1
	SLC19A1	ENST00000380010.8	TSL:1	c.696T>C	p.Pro232Pro	synonymous	Exon 3 of 6	ENSP00000369347.4

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86981 AN: 152064 Hom.: 24974 Cov.: 35

Gnomad AFR AF: 0.553

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.588

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.556

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.542

GnomAD2 exomes AF: 0.578 AC: 142920 AN: 247472 AF XY: 0.582

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.579

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.478

Gnomad FIN exome AF: 0.560

Gnomad NFE exome AF: 0.580

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.578 AC: 843586 AN: 1459806 Hom.: 244663 Cov.: 76 AF XY: 0.580 AC XY: 421267 AN XY: 726254

African (AFR) AF: 0.545 AC: 18230 AN: 33470

American (AMR) AF: 0.579 AC: 25862 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 16071 AN: 26094

East Asian (EAS) AF: 0.454 AC: 18021 AN: 39690

South Asian (SAS) AF: 0.637 AC: 54967 AN: 86232

European-Finnish (FIN) AF: 0.557 AC: 28867 AN: 51786

Middle Eastern (MID) AF: 0.519 AC: 2990 AN: 5766

European-Non Finnish (NFE) AF: 0.579 AC: 643982 AN: 1111736

Other (OTH) AF: 0.573 AC: 34596 AN: 60354

GnomAD4 genome AF: 0.572 AC: 87084 AN: 152182 Hom.: 25021 Cov.: 35 AF XY: 0.571 AC XY: 42515 AN XY: 74398

African (AFR) AF: 0.554 AC: 22980 AN: 41514

American (AMR) AF: 0.589 AC: 9009 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2157 AN: 3468

East Asian (EAS) AF: 0.474 AC: 2449 AN: 5162

South Asian (SAS) AF: 0.641 AC: 3095 AN: 4832

European-Finnish (FIN) AF: 0.556 AC: 5898 AN: 10608

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.582 AC: 39555 AN: 67976

Other (OTH) AF: 0.547 AC: 1157 AN: 2114

Alfa AF: 0.578 Hom.: 53835

Bravo AF: 0.572

Asia WGS AF: 0.564 AC: 1963 AN: 3478

EpiCase AF: 0.574

EpiControl AF: 0.576

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.43
DANN	Benign	0.31
PhyloP100		-6.6
PromoterAI		-0.024	Neutral
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: rs12659; hg19: chr21-46951556; COSMIC: COSV60753605; COSMIC: COSV60753605;