Genetic Variant SLC19A1:p.His27Leu (chr21-45537880-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is . The variant received 2 ACMG points: 2P and 0B. PM2

The NM_194255.4(SLC19A1):c.80A>T(p.His27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/22 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: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC19A1
NM_194255.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.987

Publications

0 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 Gene-Disease associations (from GenCC):

combined immunodeficiency
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
immunodeficiency 114, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: ClinGen
megaloblastic anemia, folate-responsive
Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

SLC19A1 links:

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new If you want to explore the variant's impact on the transcript NM_194255.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	UniProt
SLC19A1	NM_194255.4	MANE Select	c.80A>T	p.His27Leu	missense	Exon 2 of 6	NP_919231.1	P41440-1
SLC19A1	NM_001352512.2		c.80A>T	p.His27Leu	missense	Exon 2 of 6	NP_001339441.1	P41440-1
SLC19A1	NM_001205206.4		c.80A>T	p.His27Leu	missense	Exon 2 of 6	NP_001192135.1	P41440-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A1	ENST00000311124.9	TSL:1 MANE Select	c.80A>T	p.His27Leu	missense	Exon 2 of 6	ENSP00000308895.4	P41440-1
SLC19A1	ENST00000567670.5	TSL:1	c.80A>T	p.His27Leu	missense	Exon 2 of 6	ENSP00000457278.1	H3BTQ3
SLC19A1	ENST00000380010.8	TSL:1	c.80A>T	p.His27Leu	missense	Exon 2 of 6	ENSP00000369347.4	P41440-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1448858

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719954

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:

0.00

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

3.7

(source)

DANN

Benign

0.39

DEOGEN2

Benign

0.13

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.17

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.078

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-1.3

PhyloP100

0.99

PrimateAI

Benign

0.30

PROVEAN

Benign

0.86

REVEL

Uncertain

0.33

Sift

Benign

0.64

Sift4G

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.032

gMVP

0.37

Mutation Taster

=100/0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over