rs12327843

Positions:

• chr19-17894103-T-C

Variant summary

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

The NM_000453.3(SLC5A5):​c.*226T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 517,946 control chromosomes in the GnomAD database, including 13,368 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3961 hom., cov: 30)
  • Exomes 𝑓: 0.21 (9407 hom.)
• Consequence: SLC5A5 NM_000453.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.04

Genes affected

SLC5A5 (HGNC:11040): (solute carrier family 5 member 5) This gene encodes a member of the sodium glucose cotransporter family. The encoded protein is responsible for the uptake of iodine in tissues such as the thyroid and lactating breast tissue. The iodine taken up by the thyroid is incorporated into the metabolic regulators triiodothyronine (T3) and tetraiodothyronine (T4). Mutations in this gene are associated with thyroid dyshormonogenesis 1.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 19-17894103-T-C is Benign according to our data. Variant chr19-17894103-T-C is described in ClinVar as [Benign]. Clinvar id is 328548.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.24 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC5A5	NM_000453.3	c.*226T>C		3_prime_UTR_variant	15/15	ENST00000222248.4	NP_000444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC5A5	ENST00000222248.4	c.*226T>C		3_prime_UTR_variant	15/15	1	NM_000453.3	ENSP00000222248	P1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33295 AN: 151078 Hom.: 3949 Cov.: 30

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.214 AC: 78500 AN: 366778 Hom.: 9407 Cov.: 3 AF XY: 0.209 AC XY: 40518 AN XY: 193646

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.260

Gnomad4 EAS exome AF: 0.0322

Gnomad4 SAS exome AF: 0.114

Gnomad4 FIN exome AF: 0.269

Gnomad4 NFE exome AF: 0.245

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.221 AC: 33350 AN: 151168 Hom.: 3961 Cov.: 30 AF XY: 0.218 AC XY: 16097 AN XY: 73836

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.188

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.0115

Gnomad4 SAS AF: 0.112

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.224

Alfa AF: 0.234 Hom.: 8641

Bravo AF: 0.216

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 19, 2021	- -

Thyroid dyshormonogenesis 1 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.075
DANN	Benign	0.29

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: rs12327843; hg19: chr19-18004912;