8-109087754-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_003301.7(TRHR):c.242C>G(p.Pro81Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRHR NM_003301.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.90

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant 8-109087754-C-G is Pathogenic according to our data. Variant chr8-109087754-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 689395.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.242C>G	p.Pro81Arg	missense_variant	2/3	ENST00000518632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRHR	ENST00000518632.2	c.242C>G	p.Pro81Arg	missense_variant	2/3	5	NM_003301.7	P1
TRHR	ENST00000311762.2	c.242C>G	p.Pro81Arg	missense_variant	1/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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, PP3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 05, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.47	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.3	D;D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.98
MutPred		0.77		Gain of methylation at P81 (P = 0.0345);Gain of methylation at P81 (P = 0.0345);
MVP		0.98
MPC		0.84
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.87
gMVP		0.90

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

Publications

LitVar

Other links and lift over

dbSNP: rs1586182837; hg19: chr8-110099983;