19-17894103-T-G

Variant names:

• chr19-17894103-T-G
• rs12327843
• NM_000453.3:c.*226T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000453.3(SLC5A5):​c.*226T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000817 in 367,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: SLC5A5 NM_000453.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC5A5	NM_000453.3	c.*226T>G		3_prime_UTR_variant	Exon 15 of 15	ENST00000222248.4	NP_000444.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC5A5	ENST00000222248.4	c.*226T>G		3_prime_UTR_variant	Exon 15 of 15	1	NM_000453.3	ENSP00000222248.2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000817 AC: 3 AN: 367360 Hom.: 0 Cov.: 3 AF XY: 0.0000103 AC XY: 2 AN XY: 193956

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 9988

American (AMR) AF: 0.00 AC: 0 AN: 14360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11236

East Asian (EAS) AF: 0.00 AC: 0 AN: 23638

South Asian (SAS) AF: 0.00 AC: 0 AN: 38124

European-Finnish (FIN) AF: 0.0000836 AC: 2 AN: 23920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1588

European-Non Finnish (NFE) AF: 0.00000448 AC: 1 AN: 223358

Other (OTH) AF: 0.00 AC: 0 AN: 21148

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.067
DANN	Benign	0.40
PhyloP100		-1.0

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: rs12327843; hg19: chr19-18004912;