1-169468154-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006996.3(SLC19A2):c.1322T>C(p.Ile441Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00147 in 1,614,006 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 71 hom. )

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.15

Publications

7 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010354489).

BP6

Variant 1-169468154-A-G is Benign according to our data. Variant chr1-169468154-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281210.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006996.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	NM_006996.3	MANE Select	c.1322T>C	p.Ile441Thr	missense	Exon 5 of 6	NP_008927.1
	SLC19A2	NM_001319667.1		c.719T>C	p.Ile240Thr	missense	Exon 4 of 5	NP_001306596.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.1322T>C	p.Ile441Thr	missense	Exon 5 of 6	ENSP00000236137.5
SLC19A2	ENST00000367804.4	TSL:1	c.719T>C	p.Ile240Thr	missense	Exon 4 of 5	ENSP00000356778.3
SLC19A2	ENST00000646596.1		c.1223T>C	p.Ile408Thr	missense	Exon 5 of 6	ENSP00000494404.1

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

371

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0634

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00512

AC:

1286

AN:

251382

AF XY:

0.00472

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0673

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00138

AC:

2011

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

938

AN XY:

727150

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33474

American (AMR)

AF:

0.000201

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0388

AC:

1542

AN:

39694

South Asian (SAS)

AF:

0.00107

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000162

AC:

AN:

1111886

Other (OTH)

AF:

0.00571

AC:

345

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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

AF:

0.00241

AC:

367

AN:

152288

Hom.:

Cov.:

AF XY:

0.00266

AC XY:

198

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41556

American (AMR)

AF:

0.000719

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0628

AC:

325

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00155

Hom.:

Bravo

AF:

0.00270

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00458

AC:

556

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (2)

not provided (2)

not specified (2)

Thiamine-responsive megaloblastic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

MetaRNN

Benign

0.010

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.6

PhyloP100

7.2

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.65

Sift

Benign

0.031

Sift4G

Uncertain

0.045

Polyphen

0.88

Vest4

0.68

MVP

0.90

MPC

0.26

ClinPred

0.029

GERP RS

5.4

Varity_R

0.27

gMVP

0.48

Mutation Taster

=86/14

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over