NM_006996.3:c.*1543_*1546delCTGT

Variant names:

• chr1-169464302-AACAG-A
• rs886045522
• NM_006996.3:c.*1543_*1546delCTGT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_006996.3(SLC19A2):​c.*1543_*1546delCTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 152,306 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.00012 (0 hom., cov: 32)
• Consequence: SLC19A2 NM_006996.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.271
• Publications: 0 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000125 (19/152306) while in subpopulation EAS AF = 0.00193 (10/5190). AF 95% confidence interval is 0.00104. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*1543_*1546delCTGT		3_prime_UTR	Exon 6 of 6	NP_008927.1	O60779-1
	SLC19A2	NM_001319667.1		c.*1543_*1546delCTGT		3_prime_UTR	Exon 5 of 5	NP_001306596.1	A0A024R8Y5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.*1543_*1546delCTGT		3_prime_UTR	Exon 6 of 6	ENSP00000236137.5	O60779-1
	SLC19A2	ENST00000367804.4	TSL:1	c.*1543_*1546delCTGT		3_prime_UTR	Exon 5 of 5	ENSP00000356778.3	O60779-2
	SLC19A2	ENST00000646596.1		c.*1543_*1546delCTGT		3_prime_UTR	Exon 6 of 6	ENSP00000494404.1	A0A2R8Y5B5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74468

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000110

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (1)
-	1	-	Thiamine-responsive megaloblastic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.27

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: rs886045522; hg19: chr1-169433540;