Genetic Variant SLC19A1:p.Asp522His (chr21-45515870-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_194255.4(SLC19A1):c.1564G>C(p.Asp522His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,428,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D522N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

SLC19A1
NM_194255.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

3 publications found

Variant links:

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]

SLC19A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13573161).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A1	NM_194255.4 link	c.1564G>C	p.Asp522His	missense_variant	Exon 6 of 6	ENST00000311124.9	NP_919231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A1	ENST00000311124.9 link	c.1564G>C	p.Asp522His	missense_variant	Exon 6 of 6	1	NM_194255.4	ENSP00000308895.4		P41440-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000973

AC:

AN:

205522

AF XY:

0.0000179

show subpopulations

Gnomad AFR exome

AF:

0.0000730

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000273

AC:

AN:

1428072

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

707000

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32728

American (AMR)

AF:

0.00

AC:

AN:

40316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24030

East Asian (EAS)

AF:

0.00

AC:

AN:

39064

South Asian (SAS)

AF:

0.00

AC:

AN:

81892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.0000338

AC:

AN:

1094498

Other (OTH)

AF:

0.0000170

AC:

AN:

58794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000829

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.034

T;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.

PhyloP100

1.4

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.15

Sift

Uncertain

0.013

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.99

D;.

Vest4

0.17

MutPred

0.070

Loss of helix (P = 0.0558);.;

MVP

0.31

MPC

0.55

ClinPred

0.27

GERP RS

2.8

Varity_R

0.089

gMVP

0.18

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over