Genetic Variant NM_194255.4:c.80A>C (chr21-45537880-T-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.80A>C(p.His27Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,858 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. H27R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SLC19A1
NM_194255.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.987

Publications

403 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=0.17784226).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC19A1	NM_194255.4	MANE Select	c.80A>C	p.His27Pro	missense	Exon 2 of 6	NP_919231.1
SLC19A1	NM_001352512.2		c.80A>C	p.His27Pro	missense	Exon 2 of 6	NP_001339441.1
SLC19A1	NM_001205206.4		c.80A>C	p.His27Pro	missense	Exon 2 of 6	NP_001192135.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.80A>C	p.His27Pro	missense	Exon 2 of 6	ENSP00000308895.4
SLC19A1	ENST00000567670.5	TSL:1	c.80A>C	p.His27Pro	missense	Exon 2 of 6	ENSP00000457278.1
SLC19A1	ENST00000380010.8	TSL:1	c.80A>C	p.His27Pro	missense	Exon 2 of 6	ENSP00000369347.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000437

AC:

AN:

228958

AF XY:

0.00000803

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000580

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448858

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719954

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33392

American (AMR)

AF:

0.00

AC:

AN:

43486

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25934

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39332

South Asian (SAS)

AF:

0.00

AC:

AN:

84514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1107912

Other (OTH)

AF:

0.00

AC:

AN:

59984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.079

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.17

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.29

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.69

MutationAssessor

Benign

0.0

PhyloP100

0.99

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.34

Sift

Benign

0.20

Sift4G

Benign

0.20

Polyphen

0.0040

Vest4

0.10

MutPred

0.46

Gain of catalytic residue at H27 (P = 0.0695)

MVP

0.84

MPC

0.15

ClinPred

0.0072

GERP RS

2.8

Varity_R

0.10

gMVP

0.72

Mutation Taster

=95/5

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over