rs121909179

Variant names:

• chr19-17888432-G-A
• rs121909179
• NM_000453.3:c.1628G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000453.3(SLC5A5):​c.1628G>A​(p.Gly543Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SLC5A5 NM_000453.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.00
• Publications: 21 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 19-17888432-G-A is Pathogenic according to our data. Variant chr19-17888432-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 7669.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1628G>A	p.Gly543Glu	missense	Exon 13 of 15	NP_000444.1	Q92911
	SLC5A5	NM_001440707.1		c.1361G>A	p.Gly454Glu	missense	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.1628G>A	p.Gly543Glu	missense	Exon 13 of 15	ENSP00000222248.2	Q92911
	SLC5A5	ENST00000597109.1	TSL:4	n.*54G>A		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Thyroid dyshormonogenesis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.0	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.89		Loss of catalytic residue at A544 (P = 0.1187)
MVP		0.93
MPC		0.85
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.79
gMVP		0.96
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs121909179; hg19: chr19-17999241; COSMIC: COSV55832403; COSMIC: COSV55832403;