1-169468942-A-G

Variant names:

• chr1-169468942-A-G
• rs3737683
• NM_006996.3:c.1031-106T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006996.3(SLC19A2):​c.1031-106T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 982,534 control chromosomes in the GnomAD database, including 1,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (373 hom., cov: 32)
  • Exomes 𝑓: 0.051 (1382 hom.)
• Consequence: SLC19A2 NM_006996.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.499
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-169468942-A-G is Benign according to our data. Variant chr1-169468942-A-G is described in ClinVar as [Benign]. Clinvar id is 676194.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.1031-106T>C		intron_variant	Intron 3 of 5	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.428-106T>C		intron_variant	Intron 2 of 4		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.1031-106T>C		intron_variant	Intron 3 of 5	1	NM_006996.3	ENSP00000236137.5
SLC19A2	ENST00000367804.4	c.428-106T>C		intron_variant	Intron 2 of 4	1		ENSP00000356778.3
SLC19A2	ENST00000643377.1	n.256T>C		non_coding_transcript_exon_variant	Exon 1 of 2
SLC19A2	ENST00000646596.1	c.1031-205T>C		intron_variant	Intron 3 of 5			ENSP00000494404.1

Frequencies

GnomAD3 genomes AF: 0.0614 AC: 9347 AN: 152136 Hom.: 372 Cov.: 32

Gnomad AFR AF: 0.0957

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0529

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.00489

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0432

Gnomad OTH AF: 0.0579

GnomAD4 exome AF: 0.0509 AC: 42301 AN: 830280 Hom.: 1382 Cov.: 11 AF XY: 0.0520 AC XY: 22468 AN XY: 432192

African (AFR) AF: 0.103 AC: 2048 AN: 19802

American (AMR) AF: 0.0392 AC: 1284 AN: 32766

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 2468 AN: 20966

East Asian (EAS) AF: 0.0944 AC: 3155 AN: 33432

South Asian (SAS) AF: 0.0726 AC: 4756 AN: 65502

European-Finnish (FIN) AF: 0.00681 AC: 286 AN: 41990

Middle Eastern (MID) AF: 0.111 AC: 338 AN: 3052

European-Non Finnish (NFE) AF: 0.0443 AC: 25388 AN: 573610

Other (OTH) AF: 0.0658 AC: 2578 AN: 39160

GnomAD4 genome AF: 0.0614 AC: 9356 AN: 152254 Hom.: 373 Cov.: 32 AF XY: 0.0610 AC XY: 4541 AN XY: 74464

African (AFR) AF: 0.0957 AC: 3973 AN: 41526

American (AMR) AF: 0.0528 AC: 807 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3472

East Asian (EAS) AF: 0.120 AC: 622 AN: 5180

South Asian (SAS) AF: 0.0795 AC: 384 AN: 4828

European-Finnish (FIN) AF: 0.00489 AC: 52 AN: 10626

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0432 AC: 2940 AN: 68022

Other (OTH) AF: 0.0592 AC: 125 AN: 2112

Alfa AF: 0.0502 Hom.: 22

Bravo AF: 0.0665

Asia WGS AF: 0.0970 AC: 338 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.7
DANN	Benign	0.77
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3737683; hg19: chr1-169438180;