19-17883764-A-C

Variant names:

• chr19-17883764-A-C
• rs73520743
• NM_000453.3:c.1326A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000453.3(SLC5A5):​c.1326A>C​(p.Thr442Thr) 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 Likely 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/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -6.63
• Publications: 5 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: G2P, PanelApp Australia, Ambry Genetics, 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=-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/Likely_benign. ClinVar VariationId is 256195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.1326A>C	p.Thr442Thr	synonymous	Exon 11 of 15	NP_000444.1	Q92911
	SLC5A5	NM_001440707.1		c.1059A>C	p.Thr353Thr	synonymous	Exon 12 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.1326A>C	p.Thr442Thr	synonymous	Exon 11 of 15	ENSP00000222248.2	Q92911
	SLC5A5	ENST00000597109.1	TSL:4	n.325A>C		non_coding_transcript_exon	Exon 2 of 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

GnomAD2 exomes AF: 0.00973 AC: 2387 AN: 245368 AF XY: 0.00746

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 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

African (AFR) AF: 0.204 AC: 4285 AN: 20982

American (AMR) AF: 0.0101 AC: 377 AN: 37188

Ashkenazi Jewish (ASJ) AF: 0.00834 AC: 122 AN: 14624

East Asian (EAS) AF: 0.00 AC: 0 AN: 14876

South Asian (SAS) AF: 0.000232 AC: 17 AN: 73306

European-Finnish (FIN) AF: 0.0000295 AC: 1 AN: 33842

Middle Eastern (MID) AF: 0.0180 AC: 64 AN: 3554

European-Non Finnish (NFE) AF: 0.00151 AC: 748 AN: 495618

Other (OTH) AF: 0.0214 AC: 617 AN: 28794

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

African (AFR) AF: 0.166 AC: 5216 AN: 31342

American (AMR) AF: 0.0228 AC: 216 AN: 9484

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 7 AN: 2958

East Asian (EAS) AF: 0.00 AC: 0 AN: 3182

South Asian (SAS) AF: 0.00 AC: 0 AN: 2840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4494

Middle Eastern (MID) AF: 0.0135 AC: 3 AN: 222

European-Non Finnish (NFE) AF: 0.00113 AC: 63 AN: 55688

Other (OTH) AF: 0.0341 AC: 52 AN: 1526

Alfa AF: 0.0228 Hom.: 88

Bravo AF: 0.0439

Asia WGS AF: 0.0100 AC: 38 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Thyroid dyshormonogenesis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.13
DANN	Benign	0.54
PhyloP100		-6.6
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: rs73520743; hg19: chr19-17994573;