8-132867054-G-C

Variant names:

• chr8-132867054-G-C
• rs145163419
• NM_003235.5:c.54G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_003235.5(TG):​c.54G>C​(p.Ser18Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,447,416 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. Synonymous variant affecting the same amino acid position (i.e. S18S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TG NM_003235.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.87
• Publications: 0 publications found

Genes affected

TG (HGNC:11764): (thyroglobulin) Thyroglobulin (Tg) is a glycoprotein homodimer produced predominantly by the thryroid gland. It acts as a substrate for the synthesis of thyroxine and triiodothyronine as well as the storage of the inactive forms of thyroid hormone and iodine. Thyroglobulin is secreted from the endoplasmic reticulum to its site of iodination, and subsequent thyroxine biosynthesis, in the follicular lumen. Mutations in this gene cause thyroid dyshormonogenesis, manifested as goiter, and are associated with moderate to severe congenital hypothyroidism. Polymorphisms in this gene are associated with susceptibility to autoimmune thyroid diseases (AITD) such as Graves disease and Hashimoto thryoiditis. [provided by RefSeq, Nov 2009]

TG Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 3

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP7: Synonymous conserved (PhyloP=-2.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TG	NM_003235.5	c.54G>C	p.Ser18Ser	synonymous_variant	Exon 1 of 48	ENST00000220616.9	NP_003226.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TG	ENST00000220616.9	c.54G>C	p.Ser18Ser	synonymous_variant	Exon 1 of 48	1	NM_003235.5	ENSP00000220616.4
TG	ENST00000523901.1	n.54G>C		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000427871.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1447416 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 718404

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 43492

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25814

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.00 AC: 0 AN: 83726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103938

Other (OTH) AF: 0.00 AC: 0 AN: 59792

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.015
DANN	Benign	0.33
PhyloP100		-2.9
PromoterAI		-0.027	Neutral

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: rs145163419; hg19: chr8-133879299;