8-109088252-T-C

Variant names:

• chr8-109088252-T-C
• NM_003301.7:c.740T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003301.7(TRHR):​c.740T>C​(p.Val247Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRHR NM_003301.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06802845).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRHR	NM_003301.7	c.740T>C	p.Val247Ala	missense_variant	Exon 2 of 3	ENST00000518632.2	NP_003292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRHR	ENST00000518632.2	c.740T>C	p.Val247Ala	missense_variant	Exon 2 of 3	5	NM_003301.7	ENSP00000430711.2
TRHR	ENST00000311762.2	c.740T>C	p.Val247Ala	missense_variant	Exon 1 of 2	1		ENSP00000309818.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.740T>C (p.V247A) alteration is located in exon 1 (coding exon 1) of the TRHR gene. This alteration results from a T to C substitution at nucleotide position 740, causing the valine (V) at amino acid position 247 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.37
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.23	.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.53	N;N
REVEL	Benign	0.10
Sift	Benign	0.79	T;T
Sift4G	Benign	0.82	T;T
Polyphen		0.0	B;B
Vest4		0.043
MutPred		0.37		Loss of stability (P = 0.0279);Loss of stability (P = 0.0279);
MVP		0.56
MPC		0.27
ClinPred		0.034	T
GERP RS		2.8
Varity_R		0.028
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-110100481;