rs2072757

Positions:

• chr1-169485770-G-A
• chr1-169485770-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006996.3(SLC19A2):​c.-4C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 1,529,132 control chromosomes in the GnomAD database, including 14,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2714 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11578 hom.)
• Consequence: SLC19A2 NM_006996.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.348

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 1-169485770-G-A is Benign according to our data. Variant chr1-169485770-G-A is described in ClinVar as [Benign]. Clinvar id is 130317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-169485770-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.-4C>T		5_prime_UTR_variant	1/6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.-4C>T		5_prime_UTR_variant	1/5		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.-4C>T		5_prime_UTR_variant	1/6	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.-4C>T		5_prime_UTR_variant	1/5	1		ENSP00000356778.3
SLC19A2	ENST00000646596.1	c.-4C>T		5_prime_UTR_variant	1/6			ENSP00000494404.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 25326 AN: 151846 Hom.: 2700 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.134

Gnomad SAS AF: 0.198

Gnomad FIN AF: 0.0631

Gnomad MID AF: 0.207

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.150 AC: 18931 AN: 126022 Hom.: 1690 AF XY: 0.154 AC XY: 10624 AN XY: 69144

Gnomad AFR exome AF: 0.310

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.128

Gnomad SAS exome AF: 0.200

Gnomad FIN exome AF: 0.0695

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.150

GnomAD4 exome AF: 0.119 AC: 164237 AN: 1377168 Hom.: 11578 Cov.: 32 AF XY: 0.122 AC XY: 82666 AN XY: 679138

Gnomad4 AFR exome AF: 0.301

Gnomad4 AMR exome AF: 0.134

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.106

Gnomad4 SAS exome AF: 0.198

Gnomad4 FIN exome AF: 0.0646

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.146

GnomAD4 genome AF: 0.167 AC: 25375 AN: 151964 Hom.: 2714 Cov.: 32 AF XY: 0.165 AC XY: 12238 AN XY: 74290

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.153

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.198

Gnomad4 FIN AF: 0.0631

Gnomad4 NFE AF: 0.107

Gnomad4 OTH AF: 0.169

Alfa AF: 0.146 Hom.: 378

Bravo AF: 0.177

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Thiamine-responsive megaloblastic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2072757; hg19: chr1-169455008;