8-109088045-C-A

Position:

• chr8-109088045-C-A

Variant summary

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

The NM_003301.7(TRHR):​c.533C>A​(p.Ser178Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 1.95

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRHR	NM_003301.7	c.533C>A	p.Ser178Tyr	missense_variant	2/3	ENST00000518632.2	NP_003292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRHR	ENST00000518632.2	c.533C>A	p.Ser178Tyr	missense_variant	2/3	5	NM_003301.7	ENSP00000430711	P1
TRHR	ENST00000311762.2	c.533C>A	p.Ser178Tyr	missense_variant	1/2	1		ENSP00000309818	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.533C>A (p.S178Y) alteration is located in exon 1 (coding exon 1) of the TRHR gene. This alteration results from a C to A substitution at nucleotide position 533, causing the serine (S) at amino acid position 178 to be replaced by a tyrosine (Y). 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	0.18
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	.;T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.78	T
MutationTaster	Benign	0.74	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.92	P;P
Vest4		0.31
MutPred		0.77		Loss of glycosylation at S178 (P = 0.0679);Loss of glycosylation at S178 (P = 0.0679);
MVP		0.60
MPC		0.69
ClinPred		0.93	D
GERP RS		4.3
Varity_R		0.17
gMVP		0.79

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: chr8-110100274;