Genetic Variant SLC19A2:p.Gly172Ala (chr1-169477447-C-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_006996.3(SLC19A2):c.515G>C(p.Gly172Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G172D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

SLC19A2
NM_006996.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

1 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Orphanet

SLC19A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-169477447-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 5957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	NM_006996.3	MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 2 of 6	NP_008927.1	O60779-1
	SLC19A2	NM_001319667.1		c.205-7261G>C		intron	N/A	NP_001306596.1	A0A024R8Y5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.515G>C	p.Gly172Ala	missense	Exon 2 of 6	ENSP00000236137.5	O60779-1
SLC19A2	ENST00000367804.4	TSL:1	c.205-7261G>C		intron	N/A	ENSP00000356778.3	O60779-2
SLC19A2	ENST00000646596.1		c.515G>C	p.Gly172Ala	missense	Exon 2 of 6	ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.33

MutationAssessor

Benign

1.2

PhyloP100

7.6

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.69

Sift

Benign

0.41

Sift4G

Benign

0.60

Polyphen

0.55

Vest4

0.80

MutPred

0.69

Loss of catalytic residue at S173 (P = 0.3157)

MVP

0.86

MPC

0.65

ClinPred

0.96

GERP RS

5.3

Varity_R

0.30

gMVP

0.78

Mutation Taster

=14/86

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over