NM_003301.7:c.789+1245G>T

Variant names:

• chr8-109089546-G-T
• rs3134106
• NM_003301.7:c.789+1245G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003301.7(TRHR):​c.789+1245G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.155 in 151,950 control chromosomes in the GnomAD database, including 2,390 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2390 hom., cov: 32)
• Consequence: TRHR NM_003301.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.313
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.302 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRHR	NM_003301.7	MANE Select	c.789+1245G>T		intron	N/A	NP_003292.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRHR	ENST00000518632.2	TSL:5 MANE Select	c.789+1245G>T		intron	N/A	ENSP00000430711.2
	TRHR	ENST00000311762.2	TSL:1	c.789+1245G>T		intron	N/A	ENSP00000309818.2

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23540 AN: 151832 Hom.: 2385 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.0769

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.0565

Gnomad SAS AF: 0.121

Gnomad FIN AF: 0.191

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.187

Gnomad OTH AF: 0.187

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.155 AC: 23557 AN: 151950 Hom.: 2390 Cov.: 32 AF XY: 0.158 AC XY: 11722 AN XY: 74248

African (AFR) AF: 0.0552 AC: 2289 AN: 41476

American (AMR) AF: 0.310 AC: 4726 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 439 AN: 3466

East Asian (EAS) AF: 0.0568 AC: 293 AN: 5154

South Asian (SAS) AF: 0.120 AC: 579 AN: 4812

European-Finnish (FIN) AF: 0.191 AC: 2012 AN: 10532

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.187 AC: 12710 AN: 67938

Other (OTH) AF: 0.186 AC: 392 AN: 2108

Alfa AF: 0.131 Hom.: 372

Bravo AF: 0.158

Asia WGS AF: 0.0750 AC: 261 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.2
DANN	Benign	0.45
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3134106; hg19: chr8-110101775;