rs75099879

chr1-169477166-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006996.3(SLC19A2):c.796G>A(p.Val266Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00128 in 1,613,658 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0069 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (8 hom.)
• Consequence: SLC19A2 NM_006996.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -2.48

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035036802).
• BP6: Variant 1-169477166-C-T is Benign according to our data. Variant chr1-169477166-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 293525.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00692 (1054/152288) while in subpopulation AFR AF= 0.024 (996/41538). AF 95% confidence interval is 0.0227. There are 12 homozygotes in gnomad4. There are 532 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC19A2	NM_006996.3	c.796G>A	p.Val266Met	missense_variant	2/6	ENST00000236137.10
SLC19A2	NM_001319667.1	c.205-6980G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC19A2	ENST00000236137.10	c.796G>A	p.Val266Met	missense_variant	2/6	1	NM_006996.3	P1
SLC19A2	ENST00000367804.4	c.205-6980G>A		intron_variant		1
SLC19A2	ENST00000646596.1	c.796G>A	p.Val266Met	missense_variant	2/6

Frequencies

GnomAD3 genomes AF: 0.00689 AC: 1049 AN: 152170 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00190 AC: 477 AN: 250962 Hom.: 6 AF XY: 0.00164 AC XY: 223 AN XY: 135798

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.000687 AC: 1004 AN: 1461370 Hom.: 8 Cov.: 34 AF XY: 0.000607 AC XY: 441 AN XY: 727016

Gnomad4 AFR exome AF: 0.0212

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000115

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00692 AC: 1054 AN: 152288 Hom.: 12 Cov.: 32 AF XY: 0.00714 AC XY: 532 AN XY: 74472

Gnomad4 AFR AF: 0.0240

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00134 Hom.: 4

Bravo AF: 0.00796

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0247 AC: 109

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00231 AC: 281

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 2016	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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 25, 2021	- -

Thiamine-responsive megaloblastic anemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 02, 2018

ACMG criteria: PP3 (2 predictors), BP4 (9 predictors), BS1 (2.51% in ExAC African population), BS2 (10 homozygotes in gnomAD), BP6 (GeneDx calls benign)=benign -

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

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

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.0020
Dann	Benign	0.83
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.30	T;.;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.49	N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.0	N;.;.
REVEL	Benign	0.26
Sift	Benign	0.14	T;.;.
Sift4G	Benign	0.14	T;.;.
Polyphen		0.0020	B;B;.
Vest4		0.13
MVP		0.32
MPC		0.17
ClinPred		0.0065	T
GERP RS		-11
Varity_R		0.021
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs75099879; hg19: chr1-169446404;