rs4808708

chr19-17890877-G-A

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.1652-9G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,597,824 control chromosomes in the GnomAD database, including 38,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (3029 hom., cov: 31)
  • Exomes 𝑓: 0.22 (35820 hom.)
• Consequence: SLC5A5 NM_000453.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005823
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.00600

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=-0.87).
• BP6: Variant 19-17890877-G-A is Benign according to our data. Variant chr19-17890877-G-A is described in ClinVar as [Benign]. Clinvar id is 256199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17890877-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.232 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A5	NM_000453.3	c.1652-9G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000222248.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A5	ENST00000222248.4	c.1652-9G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000453.3	P1

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28314 AN: 151740 Hom.: 3026 Cov.: 31

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.236

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.179 AC: 44669 AN: 249144 Hom.: 4836 AF XY: 0.183 AC XY: 24730 AN XY: 134832

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.114

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.00669

Gnomad SAS exome AF: 0.123

Gnomad FIN exome AF: 0.254

Gnomad NFE exome AF: 0.231

Gnomad OTH exome AF: 0.196

GnomAD4 exome AF: 0.216 AC: 312877 AN: 1445966 Hom.: 35820 Cov.: 29 AF XY: 0.214 AC XY: 154331 AN XY: 720230

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.122

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.0258

Gnomad4 SAS exome AF: 0.130

Gnomad4 FIN exome AF: 0.246

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.202

GnomAD4 genome AF: 0.187 AC: 28336 AN: 151858 Hom.: 3029 Cov.: 31 AF XY: 0.185 AC XY: 13735 AN XY: 74190

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.167

Gnomad4 ASJ AF: 0.236

Gnomad4 EAS AF: 0.0118

Gnomad4 SAS AF: 0.121

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.235

Gnomad4 OTH AF: 0.190

Alfa AF: 0.222 Hom.: 4671

Bravo AF: 0.176

Asia WGS AF: 0.0890 AC: 309 AN: 3478

EpiCase AF: 0.237

EpiControl AF: 0.236

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thyroid dyshormonogenesis 1 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	2.7
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
dbscSNV1_RF	Benign	0.0
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: rs4808708; hg19: chr19-18001686;