chr19-17888430-C-T

Variant names:

• chr19-17888430-C-T
• rs45602038
• NM_000453.3:c.1626C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000453.3(SLC5A5):​c.1626C>T​(p.Cys542Cys) 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:3
• Conservation: PhyloP100: -2.46
• Publications: 7 publications found

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]

SLC5A5 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 328542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A5	NM_000453.3	c.1626C>T	p.Cys542Cys	synonymous_variant	Exon 13 of 15	ENST00000222248.4	NP_000444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A5	ENST00000222248.4	c.1626C>T	p.Cys542Cys	synonymous_variant	Exon 13 of 15	1	NM_000453.3	ENSP00000222248.2
SLC5A5	ENST00000597109.1	n.*52C>T		downstream_gene_variant		4

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

GnomAD2 exomes AF: 0.0245 AC: 6153 AN: 251280 AF XY: 0.0267

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 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

African (AFR) AF: 0.00466 AC: 156 AN: 33480

American (AMR) AF: 0.0134 AC: 599 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0474 AC: 1239 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39692

South Asian (SAS) AF: 0.0434 AC: 3745 AN: 86250

European-Finnish (FIN) AF: 0.00995 AC: 530 AN: 53242

Middle Eastern (MID) AF: 0.0492 AC: 284 AN: 5768

European-Non Finnish (NFE) AF: 0.0302 AC: 33620 AN: 1111870

Other (OTH) AF: 0.0320 AC: 1931 AN: 60388

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

African (AFR) AF: 0.00543 AC: 225 AN: 41474

American (AMR) AF: 0.0230 AC: 351 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0450 AC: 156 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5172

South Asian (SAS) AF: 0.0369 AC: 177 AN: 4800

European-Finnish (FIN) AF: 0.00699 AC: 74 AN: 10590

Middle Eastern (MID) AF: 0.0483 AC: 14 AN: 290

European-Non Finnish (NFE) AF: 0.0289 AC: 1967 AN: 67992

Other (OTH) AF: 0.0304 AC: 64 AN: 2106

Alfa AF: 0.0276 Hom.: 151

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Thyroid dyshormonogenesis 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45602038; hg19: chr19-17999239;