rs73520743

chr19-17883764-A-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000453.3(SLC5A5):c.1326A>C(p.Thr442=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 835,266 control chromosomes in the GnomAD database, including 607 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (314 hom., cov: 28)
  • Exomes 𝑓: 0.0086 (293 hom.)
• Consequence: SLC5A5 NM_000453.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -6.63

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 19-17883764-A-C is Benign according to our data. Variant chr19-17883764-A-C is described in ClinVar as [Benign]. Clinvar id is 256195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17883764-A-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-6.63 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A5	NM_000453.3	c.1326A>C	p.Thr442=	synonymous_variant	11/15	ENST00000222248.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A5	ENST00000222248.4	c.1326A>C	p.Thr442=	synonymous_variant	11/15	1	NM_000453.3	P1
SLC5A5	ENST00000597109.1	n.325A>C		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.0492 AC: 5534 AN: 112422 Hom.: 310 Cov.: 28

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.00237

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000705

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0164

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.0342

GnomAD3 exomes AF: 0.00973 AC: 2387 AN: 245368 Hom.: 127 AF XY: 0.00746 AC XY: 1002 AN XY: 134252

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.00403

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00616

GnomAD4 exome AF: 0.00862 AC: 6231 AN: 722784 Hom.: 293 Cov.: 33 AF XY: 0.00721 AC XY: 2694 AN XY: 373904

Gnomad4 AFR exome AF: 0.204

Gnomad4 AMR exome AF: 0.0101

Gnomad4 ASJ exome AF: 0.00834

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.0000295

Gnomad4 NFE exome AF: 0.00151

Gnomad4 OTH exome AF: 0.0214

GnomAD4 genome AF: 0.0494 AC: 5557 AN: 112482 Hom.: 314 Cov.: 28 AF XY: 0.0506 AC XY: 2652 AN XY: 52442

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0228

Gnomad4 ASJ AF: 0.00237

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00113

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0216 Hom.: 80

Bravo AF: 0.0439

Asia WGS AF: 0.0100 AC: 38 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00190

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Familial 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	-1.0
Cadd	Benign	0.13
Dann	Benign	0.54

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: rs73520743; hg19: chr19-17994573;