rs74315375

Variant names:

• chr1-169468793-C-T
• rs74315375
• NM_006996.3:c.1074G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_006996.3(SLC19A2):​c.1074G>A​(p.Trp358*) variant causes a stop gained 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. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC19A2 NM_006996.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-169468793-C-T is Pathogenic according to our data. Variant chr1-169468793-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 5963.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.1074G>A	p.Trp358*	stop_gained	Exon 4 of 6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.471G>A	p.Trp157*	stop_gained	Exon 3 of 5		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.1074G>A	p.Trp358*	stop_gained	Exon 4 of 6	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.471G>A	p.Trp157*	stop_gained	Exon 3 of 5	1		ENSP00000356778.3
SLC19A2	ENST00000646596.1	c.1031-56G>A		intron_variant	Intron 3 of 5			ENSP00000494404.1
SLC19A2	ENST00000643377.1	n.405G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness Pathogenic:1

Sep 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.94
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs74315375; hg19: chr1-169438031;