rs121908860

Positions:

• chr14-81143925-GC-AT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The ENST00000298171.7(TSHR):​c.1867_1868delinsAT​(p.Ala623Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A623V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSHR ENST00000298171.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.16

Genes affected

TSHR (HGNC:12373): (thyroid stimulating hormone receptor) The protein encoded by this gene is a membrane protein and a major controller of thyroid cell metabolism. The encoded protein is a receptor for thyrothropin and thyrostimulin, and its activity is mediated by adenylate cyclase. Defects in this gene are a cause of several types of hyperthyroidism. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-81143926-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3370841.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 14-81143925-GC-AT is Pathogenic according to our data. Variant chr14-81143925-GC-AT is described in ClinVar as [Pathogenic]. Clinvar id is 6432.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSHR	NM_000369.5	c.1867_1868delinsAT	p.Ala623Ile	missense_variant	10/10	ENST00000298171.7	NP_000360.2
LOC101928462	XR_001751022.2	n.487+21267_487+21268delinsAT		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSHR	ENST00000298171.7	c.1867_1868delinsAT	p.Ala623Ile	missense_variant	10/10	1	NM_000369.5	ENSP00000298171	P1
	ENST00000646052.2	n.510+21267_510+21268delinsAT		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyroid adenoma, hyperfunctioning, somatic Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 14, 1993

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121908860; hg19: chr14-81610269; COSMIC: COSV53318289;