rs45602038

chr19-17888430-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000453.3(SLC5A5):c.1626C>T(p.Cys542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.028 in 1,613,590 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 30)
  • Exomes 𝑓: 0.029 (742 hom.)
• Consequence: SLC5A5 NM_000453.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.46

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=-0.73).
• BP6: Variant 19-17888430-C-T is Benign according to our data. Variant chr19-17888430-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 328542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-17888430-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.45 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0206 (3129/152040) while in subpopulation SAS AF= 0.0369 (177/4800). AF 95% confidence interval is 0.0324. There are 53 homozygotes in gnomad4. There are 1474 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC5A5	NM_000453.3	c.1626C>T	p.Cys542=	synonymous_variant	13/15	ENST00000222248.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC5A5	ENST00000222248.4	c.1626C>T	p.Cys542=	synonymous_variant	13/15	1	NM_000453.3	P1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3128 AN: 151926 Hom.: 53 Cov.: 30

Gnomad AFR AF: 0.00544

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0450

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.00699

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0289

Gnomad OTH AF: 0.0302

GnomAD3 exomes AF: 0.0245 AC: 6153 AN: 251280 Hom.: 115 AF XY: 0.0267 AC XY: 3622 AN XY: 135818

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0424

Gnomad FIN exome AF: 0.00977

Gnomad NFE exome AF: 0.0305

Gnomad OTH exome AF: 0.0284

GnomAD4 exome AF: 0.0288 AC: 42110 AN: 1461550 Hom.: 742 Cov.: 32 AF XY: 0.0296 AC XY: 21492 AN XY: 727084

Gnomad4 AFR exome AF: 0.00466

Gnomad4 AMR exome AF: 0.0134

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0434

Gnomad4 FIN exome AF: 0.00995

Gnomad4 NFE exome AF: 0.0302

Gnomad4 OTH exome AF: 0.0320

GnomAD4 genome AF: 0.0206 AC: 3129 AN: 152040 Hom.: 53 Cov.: 30 AF XY: 0.0198 AC XY: 1474 AN XY: 74322

Gnomad4 AFR AF: 0.00543

Gnomad4 AMR AF: 0.0230

Gnomad4 ASJ AF: 0.0450

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0369

Gnomad4 FIN AF: 0.00699

Gnomad4 NFE AF: 0.0289

Gnomad4 OTH AF: 0.0304

Alfa AF: 0.0277 Hom.: 57

Bravo AF: 0.0210

Asia WGS AF: 0.0140 AC: 48 AN: 3478

EpiCase AF: 0.0318

EpiControl AF: 0.0324

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Familial thyroid dyshormonogenesis 1 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	0.22
Dann	Benign	0.45

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: rs45602038; hg19: chr19-17999239;