NM_006996.3:c.-4C>T

Variant names:

• chr1-169485770-G-A
• rs2072757
• NM_006996.3:c.-4C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.283 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	NM_006996.3	MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 6	NP_008927.1	O60779-1
	SLC19A2	NM_001319667.1		c.-4C>T		5_prime_UTR	Exon 1 of 5	NP_001306596.1	A0A024R8Y5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC19A2	ENST00000236137.10	TSL:1 MANE Select	c.-4C>T		5_prime_UTR	Exon 1 of 6	ENSP00000236137.5	O60779-1
	SLC19A2	ENST00000367804.4	TSL:1	c.-4C>T		5_prime_UTR	Exon 1 of 5	ENSP00000356778.3	O60779-2
	SLC19A2	ENST00000646596.1		c.-4C>T		5_prime_UTR	Exon 1 of 6	ENSP00000494404.1	A0A2R8Y5B5

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

GnomAD2 exomes AF: 0.150 AC: 18931 AN: 126022 AF XY: 0.154

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 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

African (AFR) AF: 0.301 AC: 9352 AN: 31102

American (AMR) AF: 0.134 AC: 4638 AN: 34712

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 6878 AN: 24768

East Asian (EAS) AF: 0.106 AC: 3749 AN: 35424

South Asian (SAS) AF: 0.198 AC: 15594 AN: 78630

European-Finnish (FIN) AF: 0.0646 AC: 2302 AN: 35622

Middle Eastern (MID) AF: 0.188 AC: 791 AN: 4208

European-Non Finnish (NFE) AF: 0.105 AC: 112540 AN: 1075316

Other (OTH) AF: 0.146 AC: 8393 AN: 57386

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

African (AFR) AF: 0.287 AC: 11883 AN: 41400

American (AMR) AF: 0.153 AC: 2338 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3470

East Asian (EAS) AF: 0.135 AC: 694 AN: 5156

South Asian (SAS) AF: 0.198 AC: 951 AN: 4814

European-Finnish (FIN) AF: 0.0631 AC: 669 AN: 10602

Middle Eastern (MID) AF: 0.205 AC: 60 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7294 AN: 67916

Other (OTH) AF: 0.169 AC: 356 AN: 2110

Alfa AF: 0.146 Hom.: 378

Bravo AF: 0.177

Asia WGS AF: 0.214 AC: 744 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Megaloblastic anemia, thiamine-responsive, with diabetes mellitus and sensorineural deafness (2)
-	-	1	not provided (1)
-	-	1	Thiamine-responsive megaloblastic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.87
PhyloP100		0.35
PromoterAI		-0.45	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=299/1	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: rs2072757; hg19: chr1-169455008;