rs7278825

chr21-45516028-G-A

Variant summary

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

The NM_194255.4(SLC19A1):c.1406C>T(p.Ala469Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,578,286 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A469S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (39 hom.)
• Consequence: SLC19A1 NM_194255.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.144

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028970242).
• BP6: Variant 21-45516028-G-A is Benign according to our data. Variant chr21-45516028-G-A is described in ClinVar as [Benign]. Clinvar id is 1652889.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-45516028-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0106 (1619/152320) while in subpopulation AFR AF= 0.0336 (1396/41568). AF 95% confidence interval is 0.0321. There are 24 homozygotes in gnomad4. There are 761 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A1	NM_194255.4	c.1406C>T	p.Ala469Val	missense_variant	6/6	ENST00000311124.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A1	ENST00000311124.9	c.1406C>T	p.Ala469Val	missense_variant	6/6	1	NM_194255.4	A2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1615 AN: 152202 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00446 AC: 824 AN: 184868 Hom.: 13 AF XY: 0.00450 AC XY: 451 AN XY: 100328

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00307

Gnomad ASJ exome AF: 0.000589

Gnomad EAS exome AF: 0.000423

Gnomad SAS exome AF: 0.0112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000778

Gnomad OTH exome AF: 0.00329

GnomAD4 exome AF: 0.00211 AC: 3006 AN: 1425966 Hom.: 39 Cov.: 36 AF XY: 0.00229 AC XY: 1617 AN XY: 705972

Gnomad4 AFR exome AF: 0.0353

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.000318

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000381

Gnomad4 OTH exome AF: 0.00399

GnomAD4 genome AF: 0.0106 AC: 1619 AN: 152320 Hom.: 24 Cov.: 34 AF XY: 0.0102 AC XY: 761 AN XY: 74476

Gnomad4 AFR AF: 0.0336

Gnomad4 AMR AF: 0.00594

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00202 Hom.: 5

Bravo AF: 0.0119

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0276 AC: 118

ESP6500EA AF: 0.000603 AC: 5

ExAC AF: 0.00443 AC: 519

Asia WGS AF: 0.00808 AC: 28 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	12
Dann	Uncertain	0.99
DEOGEN2	Benign	0.067	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.054
Sift	Benign	0.092	T;T
Sift4G	Uncertain	0.054	T;T
Polyphen		0.13	B;.
Vest4		0.019
MVP		0.26
MPC		0.13
ClinPred		0.0092	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.28

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: rs7278825; hg19: chr21-46935942; COSMIC: COSV60590130; COSMIC: COSV60590130;