8-109087855-TCAATAACAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_003301.7(TRHR):c.343_352delinsA(p.Ser115_Ala118delinsThr) variant causes a protein altering 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRHR NM_003301.7 protein_altering
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.99

Genes affected

TRHR (HGNC:12299): (thyrotropin releasing hormone receptor) This gene encodes a G protein-coupled receptor for thyrotropin-releasing hormone (TRH). Upon binding to TRH, this receptor activates the inositol phospholipid-calcium-protein kinase C transduction pathway. Mutations in this gene have been associated with generalized thyrotropin-releasing hormone resistance. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 8-109087855-TCAATAACAG-A is Pathogenic according to our data. Variant chr8-109087855-TCAATAACAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12681.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRHR	NM_003301.7	c.343_352delinsA	p.Ser115_Ala118delinsThr	protein_altering_variant	2/3	ENST00000518632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRHR	ENST00000518632.2	c.343_352delinsA	p.Ser115_Ala118delinsThr	protein_altering_variant	2/3	5	NM_003301.7	P1
TRHR	ENST00000311762.2	c.343_352delinsA	p.Ser115_Ala118delinsThr	protein_altering_variant	1/2	1		P1

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: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 7 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Feb 14, 2020	This variant is interpreted as likely pathogenic for Hypothyroidism, congenital, non-goitrous, 7, autosomal recessive. The following ACMG Tag(s) were applied: PM2, PS3, PM3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1997	- -

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: rs1586182912; hg19: chr8-110100084;