8-109087855-TCAATAACAG-A

Variant names:

• chr8-109087855-TCAATAACAG-A
• rs1586182912
• NM_003301.7:c.343_352delTCAATAACAGinsA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_003301.7(TRHR):​c.343_352delTCAATAACAGinsA​(p.Ser115_Ala118delinsThr) variant causes a missense, disruptive inframe deletion 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 missense, disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

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]

TRHR Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 7

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• resistance to thyrotropin-releasing hormone syndrome

  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
• PM4: Nonframeshift variant in NON repetitive region in NM_003301.7.
• 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 VariationId is 12681.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003301.7. 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
	TRHR	NM_003301.7	MANE Select	c.343_352delTCAATAACAGinsA	p.Ser115_Ala118delinsThr	missense disruptive_inframe_deletion	Exon 2 of 3	NP_003292.1	P34981

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRHR	ENST00000518632.2	TSL:5 MANE Select	c.343_352delTCAATAACAGinsA	p.Ser115_Ala118delinsThr	missense disruptive_inframe_deletion	Exon 2 of 3	ENSP00000430711.2	P34981
	TRHR	ENST00000311762.2	TSL:1	c.343_352delTCAATAACAGinsA	p.Ser115_Ala118delinsThr	missense disruptive_inframe_deletion	Exon 1 of 2	ENSP00000309818.2	P34981

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

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hypothyroidism, congenital, nongoitrous, 7 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10
Mutation Taster		=2/198	disease causing

Splicing

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

Other links and lift over

dbSNP: rs1586182912; hg19: chr8-110100084;