1-169464882-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006996.3(SLC19A2):c.*967A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 152,490 control chromosomes in the GnomAD database, including 4,787 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4777 hom., cov: 32)
  • Exomes 𝑓: 0.20 (10 hom.)
• Consequence: SLC19A2 NM_006996.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.432

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 1-169464882-T-C is Benign according to our data. Variant chr1-169464882-T-C is described in ClinVar as [Benign]. Clinvar id is 293513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A2	NM_006996.3	c.*967A>G		3_prime_UTR_variant	6/6	ENST00000236137.10
SLC19A2	NM_001319667.1	c.*967A>G		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A2	ENST00000236137.10	c.*967A>G		3_prime_UTR_variant	6/6	1	NM_006996.3	P1
SLC19A2	ENST00000367804.4	c.*967A>G		3_prime_UTR_variant	5/5	1
SLC19A2	ENST00000646596.1	c.*967A>G		3_prime_UTR_variant	6/6
SLC19A2	ENST00000643377.1	n.2183A>G		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.235 AC: 35658 AN: 151942 Hom.: 4762 Cov.: 32

Gnomad AFR AF: 0.375

Gnomad AMI AF: 0.155

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.123

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.174

Gnomad OTH AF: 0.211

GnomAD4 exome AF: 0.200 AC: 86 AN: 430 Hom.: 10 Cov.: 0 AF XY: 0.198 AC XY: 51 AN XY: 258

Gnomad4 FIN exome AF: 0.196

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.235 AC: 35735 AN: 152060 Hom.: 4777 Cov.: 32 AF XY: 0.232 AC XY: 17280 AN XY: 74336

Gnomad4 AFR AF: 0.375

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.190

Gnomad4 NFE AF: 0.174

Gnomad4 OTH AF: 0.212

Alfa AF: 0.191 Hom.: 3500

Bravo AF: 0.248

Asia WGS AF: 0.199 AC: 690 AN: 3460

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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	-0.69
Cadd	Benign	9.0
Dann	Benign	0.86

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: rs16862199; hg19: chr1-169434120;