8-109119324-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003301.7(TRHR):c.1066G>A(p.Val356Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00175 in 1,612,376 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: TRHR NM_003301.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.67

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074428916).
• BP6: Variant 8-109119324-G-A is Benign according to our data. Variant chr8-109119324-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 721055.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-109119324-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRHR	NM_003301.7	c.1066G>A	p.Val356Ile	missense_variant	3/3	ENST00000518632.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRHR	ENST00000518632.2	c.1066G>A	p.Val356Ile	missense_variant	3/3	5	NM_003301.7	P1
TRHR	ENST00000311762.2	c.1066G>A	p.Val356Ile	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 267 AN: 151626 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00165

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00237

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00196

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00162 AC: 406 AN: 250066 Hom.: 2 AF XY: 0.00169 AC XY: 229 AN XY: 135110

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.000726

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00200

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.00175 AC: 2558 AN: 1460634 Hom.: 4 Cov.: 31 AF XY: 0.00171 AC XY: 1240 AN XY: 726642

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.000829

Gnomad4 ASJ exome AF: 0.0000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00229

Gnomad4 NFE exome AF: 0.00198

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00176 AC: 267 AN: 151742 Hom.: 1 Cov.: 32 AF XY: 0.00171 AC XY: 127 AN XY: 74134

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.00165

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00237

Gnomad4 NFE AF: 0.00196

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00177

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00208 AC: 253

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00302

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TRHR: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.22	T;T
Eigen	Benign	-0.029
Eigen_PC	Benign	0.067
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.0074	T;T
MetaSVM	Benign	-0.69	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.16
Sift	Benign	0.077	T;T
Sift4G	Uncertain	0.038	D;D
Polyphen		0.45	B;B
Vest4		0.057
MVP		0.71
MPC		0.19
ClinPred		0.017	T
GERP RS		4.9
Varity_R		0.082
gMVP		0.28

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: rs147019235; hg19: chr8-110131553; COSMIC: COSV100304864;