rs3765227

Variant names:

• chr1-169467915-C-A
• rs3765227
• NM_006996.3:c.1365+196G>T

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.1365+196G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0414 in 152,248 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.041 (196 hom., cov: 32)
• Consequence: SLC19A2 NM_006996.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.179
• Publications: 7 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=-0.85).
• BP6: Variant 1-169467915-C-A is Benign according to our data. Variant chr1-169467915-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 673628.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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	NM_006996.3	MANE Select	c.1365+196G>T		intron	N/A	NP_008927.1
	SLC19A2	NM_001319667.1		c.762+196G>T		intron	N/A	NP_001306596.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.1365+196G>T		intron	N/A	ENSP00000236137.5
	SLC19A2	ENST00000367804.4	TSL:1	c.762+196G>T		intron	N/A	ENSP00000356778.3
	SLC19A2	ENST00000646596.1		c.1266+196G>T		intron	N/A	ENSP00000494404.1

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6300 AN: 152130 Hom.: 194 Cov.: 32

Gnomad AFR AF: 0.0266

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0443

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0786

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0428

Gnomad OTH AF: 0.0483

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

GnomAD4 genome AF: 0.0414 AC: 6304 AN: 152248 Hom.: 196 Cov.: 32 AF XY: 0.0412 AC XY: 3068 AN XY: 74446

African (AFR) AF: 0.0266 AC: 1104 AN: 41540

American (AMR) AF: 0.0442 AC: 676 AN: 15294

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

East Asian (EAS) AF: 0.120 AC: 622 AN: 5182

South Asian (SAS) AF: 0.0791 AC: 382 AN: 4828

European-Finnish (FIN) AF: 0.00481 AC: 51 AN: 10610

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0428 AC: 2914 AN: 68006

Other (OTH) AF: 0.0497 AC: 105 AN: 2112

Alfa AF: 0.0366 Hom.: 8

Bravo AF: 0.0433

Asia WGS AF: 0.0920 AC: 319 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.7
DANN	Benign	0.68
PhyloP100		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3765227; hg19: chr1-169437153;