rs17847484

Positions:

• chr1-169468154-A-C
• chr1-169468154-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006996.3(SLC19A2):​c.1322T>G​(p.Ile441Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I441T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SLC19A2 NM_006996.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.15

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.1322T>G	p.Ile441Ser	missense_variant	5/6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.719T>G	p.Ile240Ser	missense_variant	4/5		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.1322T>G	p.Ile441Ser	missense_variant	5/6	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.719T>G	p.Ile240Ser	missense_variant	4/5	1		ENSP00000356778.3
SLC19A2	ENST00000646596.1	c.1223T>G	p.Ile408Ser	missense_variant	5/6			ENSP00000494404.1
SLC19A2	ENST00000643377.1	n.1044T>G		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461722 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727154

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.7	M;.;M;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D;D;.;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;.;.
Sift4G	Uncertain	0.032	D;D;.;.
Polyphen		0.94	P;D;P;.
Vest4		0.91
MutPred		0.66		Loss of stability (P = 0.0016);.;Loss of stability (P = 0.0016);.;
MVP		0.92
MPC		0.71
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.75
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs17847484; hg19: chr1-169437392;