rs121908540

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_006996.3(SLC19A2):c.152C>T(p.Pro51Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000191 in 1,574,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 6.36

Publications

4 publications found

Variant links:

Genes affected

SLC19A2 (HGNC:10938): (solute carrier family 19 member 2) This gene encodes the thiamin transporter protein. Mutations in this gene cause thiamin-responsive megaloblastic anemia syndrome (TRMA), which is an autosomal recessive disorder characterized by diabetes mellitus, megaloblastic anemia and sensorineural deafness. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2016]

SLC19A2 Gene-Disease associations (from GenCC):

thiamine-responsive megaloblastic anemia syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp

SLC19A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A2	NM_006996.3 link	c.152C>T	p.Pro51Leu	missense_variant	Exon 1 of 6	ENST00000236137.10	NP_008927.1	O60779-1A0A024R928
SLC19A2	NM_001319667.1 link	c.152C>T	p.Pro51Leu	missense_variant	Exon 1 of 5		NP_001306596.1	O60779-2A0A024R8Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC19A2	ENST00000236137.10 link	c.152C>T	p.Pro51Leu	missense_variant	Exon 1 of 6	1	NM_006996.3	ENSP00000236137.5	O60779-1
SLC19A2	ENST00000367804.4 link	c.152C>T	p.Pro51Leu	missense_variant	Exon 1 of 5	1		ENSP00000356778.3	O60779-2
SLC19A2	ENST00000646596.1 link	c.152C>T	p.Pro51Leu	missense_variant	Exon 1 of 6			ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000112

AC:

AN:

178650

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000102

Gnomad AMR exome

AF:

0.0000350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1422006

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

703858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32424

American (AMR)

AF:

0.0000250

AC:

AN:

40000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25474

East Asian (EAS)

AF:

0.00

AC:

AN:

37314

South Asian (SAS)

AF:

0.0000123

AC:

AN:

81144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5602

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091966

Other (OTH)

AF:

0.00

AC:

AN:

58698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152218

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00000965

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.000235

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000865

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness

Pathogenic:1Uncertain:1

Mar 15, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Nov 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 51 of the SLC19A2 protein (p.Pro51Leu). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects SLC19A2 function (PMID: 17331069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC19A2 protein function. ClinVar contains an entry for this variant (Variation ID: 5964). This missense change has been observed in individual(s) with thiamine-responsive megaloblastic anemia (PMID: 14994241). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.73

T;T;.;T

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.88

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.5

M;M;M;.

PhyloP100

6.4

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-8.1

D;N;.;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0010

D;D;.;.

Sift4G

Uncertain

0.0020

D;T;.;.

Polyphen

1.0

D;D;D;.

Vest4

0.78

MVP

0.93

MPC

0.70

ClinPred

1.0

GERP RS

4.5

PromoterAI

-0.010

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.79

gMVP

0.88

Mutation Taster

=6/94

disease causing (ClinVar)

(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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rs121908540

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over