rs75099879

Positions:

chr1-169477166-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006996.3(SLC19A2):c.796G>A(p.Val266Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,658 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0069 ( 12 hom., cov: 32)

Exomes 𝑓: 0.00069 ( 8 hom. )

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -2.48

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035036802).

BP6

Variant 1-169477166-C-T is Benign according to our data. Variant chr1-169477166-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293525.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00692 (1054/152288) while in subpopulation AFR AF= 0.024 (996/41538). AF 95% confidence interval is 0.0227. There are 12 homozygotes in gnomad4. There are 532 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A2	NM_006996.3 linkuse as main transcript	c.796G>A	p.Val266Met	missense_variant	2/6	ENST00000236137.10	NP_008927.1	O60779-1A0A024R928
SLC19A2	NM_001319667.1 linkuse as main transcript	c.205-6980G>A		intron_variant			NP_001306596.1	O60779-2A0A024R8Y5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SLC19A2	ENST00000236137.10 linkuse as main transcript	c.796G>A	p.Val266Met	missense_variant	2/6	1	NM_006996.3	ENSP00000236137.5	O60779-1
SLC19A2	ENST00000367804.4 linkuse as main transcript	c.205-6980G>A		intron_variant		1		ENSP00000356778.3	O60779-2
SLC19A2	ENST00000646596.1 linkuse as main transcript	c.796G>A	p.Val266Met	missense_variant	2/6			ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes

AF:

0.00689

AC:

1049

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00222

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00190

AC:

477

AN:

250962

Hom.:

AF XY:

0.00164

AC XY:

223

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.0250

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000817

GnomAD4 exome

AF:

0.000687

AC:

1004

AN:

1461370

Hom.:

Cov.:

AF XY:

0.000607

AC XY:

441

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.0212

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000115

Gnomad4 OTH exome

AF:

0.00136

GnomAD4 genome

AF:

0.00692

AC:

1054

AN:

152288

Hom.:

Cov.:

AF XY:

0.00714

AC XY:

532

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0240

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00134

Hom.:

Bravo

AF:

0.00796

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.0247

AC:

109

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00231

AC:

281

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2021	- -

Thiamine-responsive megaloblastic anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Monogenic diabetes

Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 02, 2018

ACMG criteria: PP3 (2 predictors), BP4 (9 predictors), BS1 (2.51% in ExAC African population), BS2 (10 homozygotes in gnomAD), BP6 (GeneDx calls benign)=benign -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.0020

DANN

Benign

0.83

DEOGEN2

Benign

0.25

T;T;.

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.30

T;.;T

MetaRNN

Benign

0.0035

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.49

N;N;.

PrimateAI

Benign

0.22

PROVEAN

Benign

0.0

N;.;.

REVEL

Benign

0.26

Sift

Benign

0.14

T;.;.

Sift4G

Benign

0.14

T;.;.

Polyphen

0.0020

B;B;.

Vest4

0.13

MVP

0.32

MPC

0.17

ClinPred

0.0065

GERP RS

-11

Varity_R

0.021

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over