1-169465789-C-T

Position:

• chr1-169465789-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006996.3(SLC19A2):​c.*60G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.982 in 1,591,568 control chromosomes in the GnomAD database, including 768,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (74142 hom., cov: 31)
  • Exomes 𝑓: 0.98 (694006 hom.)
• Consequence: SLC19A2 NM_006996.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.134

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 1-169465789-C-T is Benign according to our data. Variant chr1-169465789-C-T is described in ClinVar as [Benign]. Clinvar id is 293520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC19A2	NM_006996.3	c.*60G>A		3_prime_UTR_variant	6/6	ENST00000236137.10	NP_008927.1
SLC19A2	NM_001319667.1	c.*60G>A		3_prime_UTR_variant	5/5		NP_001306596.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC19A2	ENST00000236137.10	c.*60G>A		3_prime_UTR_variant	6/6	1	NM_006996.3	ENSP00000236137	P1
SLC19A2	ENST00000367804.4	c.*60G>A		3_prime_UTR_variant	5/5	1		ENSP00000356778
SLC19A2	ENST00000646596.1	c.*60G>A		3_prime_UTR_variant	6/6			ENSP00000494404
SLC19A2	ENST00000643377.1	n.1276G>A		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes AF: 0.987 AC: 150171 AN: 152226 Hom.: 74083 Cov.: 31

Gnomad AFR AF: 0.996

Gnomad AMI AF: 0.975

Gnomad AMR AF: 0.996

Gnomad ASJ AF: 0.985

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.977

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.978

Gnomad OTH AF: 0.990

GnomAD4 exome AF: 0.982 AC: 1413344 AN: 1439224 Hom.: 694006 Cov.: 24 AF XY: 0.982 AC XY: 704919 AN XY: 717510

Gnomad4 AFR exome AF: 0.998

Gnomad4 AMR exome AF: 0.996

Gnomad4 ASJ exome AF: 0.986

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.979

Gnomad4 NFE exome AF: 0.979

Gnomad4 OTH exome AF: 0.987

GnomAD4 genome AF: 0.987 AC: 150289 AN: 152344 Hom.: 74142 Cov.: 31 AF XY: 0.987 AC XY: 73525 AN XY: 74492

Gnomad4 AFR AF: 0.996

Gnomad4 AMR AF: 0.996

Gnomad4 ASJ AF: 0.985

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.977

Gnomad4 NFE AF: 0.978

Gnomad4 OTH AF: 0.990

Alfa AF: 0.983 Hom.: 8735

Bravo AF: 0.987

Asia WGS AF: 0.999 AC: 3473 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

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. -

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	-0.77
CADD	Benign	6.3
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2678166; hg19: chr1-169435027;