dbSNP rs45602038: SLC5A5:p.Cys542Cys (chr19-17888430-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.46

Publications

7 publications found

Variant links:

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: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC5A5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000453.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A5	NM_000453.3	MANE Select	c.1626C>T	p.Cys542Cys	synonymous	Exon 13 of 15	NP_000444.1	Q92911
	SLC5A5	NM_001440707.1		c.1359C>T	p.Cys453Cys	synonymous	Exon 14 of 16	NP_001427636.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC5A5	ENST00000222248.4	TSL:1 MANE Select	c.1626C>T	p.Cys542Cys	synonymous	Exon 13 of 15	ENSP00000222248.2	Q92911
	SLC5A5	ENST00000597109.1	TSL:4	n.*52C>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.0206

AC:

3128

AN:

151926

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0296

AC XY:

21492

AN XY:

727084

show subpopulations

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:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

2237

4473

6710

8946

11183

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1280

2560

3840

5120

6400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0206

AC:

3129

AN:

152040

Hom.:

Cov.:

AF XY:

0.0198

AC XY:

1474

AN XY:

74322

show subpopulations

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:

AN:

5172

South Asian (SAS)

AF:

0.0369

AC:

177

AN:

4800

European-Finnish (FIN)

AF:

0.00699

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.0483

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0289

AC:

1967

AN:

67992

Other (OTH)

AF:

0.0304

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

150

300

449

599

749

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0276

Hom.:

151

Bravo

AF:

0.0210

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0318

EpiControl

AF:

0.0324

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Thyroid dyshormonogenesis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.22

(source)

DANN

Benign

0.45

PhyloP100

-2.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over