NM_006996.3:c.515G>C

Variant names:

• chr1-169477447-C-G
• rs28937595
• NM_006996.3:c.515G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 1 publications found

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

ACMG classification

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 [Likely_pathogenic]. Clinvar id 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.515G>C	p.Gly172Ala	missense_variant	Exon 2 of 6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.205-7261G>C		intron_variant	Intron 1 of 4		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.515G>C	p.Gly172Ala	missense_variant	Exon 2 of 6	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.205-7261G>C		intron_variant	Intron 1 of 4	1		ENSP00000356778.3
SLC19A2	ENST00000646596.1	c.515G>C	p.Gly172Ala	missense_variant	Exon 2 of 6			ENSP00000494404.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.49	T;T;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.89	D;.;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	1.2	L;L;.
PhyloP100		7.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.1	D;.;.
REVEL	Pathogenic	0.69
Sift	Benign	0.41	T;.;.
Sift4G	Benign	0.60	T;.;.
Polyphen		0.55	P;P;.
Vest4		0.80
MutPred		0.69		Loss of catalytic residue at S173 (P = 0.3157);Loss of catalytic residue at S173 (P = 0.3157);Loss of catalytic residue at S173 (P = 0.3157);
MVP		0.86
MPC		0.65
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.78
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs28937595; hg19: chr1-169446685;