chr8-109113533-T-G

Variant names:

• chr8-109113533-T-G
• rs4546626
• NM_003301.7:c.790-5515T>G

Variant summary

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

The NM_003301.7(TRHR):​c.790-5515T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 151,848 control chromosomes in the GnomAD database, including 12,344 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 0.40 (12344 hom., cov: 32)
• Consequence: TRHR NM_003301.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0510
• Publications: 4 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRHR	NM_003301.7	c.790-5515T>G		intron_variant	Intron 2 of 2	ENST00000518632.2	NP_003292.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRHR	ENST00000518632.2	c.790-5515T>G		intron_variant	Intron 2 of 2	5	NM_003301.7	ENSP00000430711.2
TRHR	ENST00000311762.2	c.790-5515T>G		intron_variant	Intron 1 of 1	1		ENSP00000309818.2

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60496 AN: 151730 Hom.: 12328 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.478

Gnomad SAS AF: 0.482

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.392

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

GnomAD4 genome AF: 0.399 AC: 60570 AN: 151848 Hom.: 12344 Cov.: 32 AF XY: 0.404 AC XY: 29968 AN XY: 74194

African (AFR) AF: 0.429 AC: 17769 AN: 41376

American (AMR) AF: 0.502 AC: 7653 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3468

East Asian (EAS) AF: 0.479 AC: 2469 AN: 5156

South Asian (SAS) AF: 0.482 AC: 2321 AN: 4816

European-Finnish (FIN) AF: 0.384 AC: 4064 AN: 10570

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24032 AN: 67916

Other (OTH) AF: 0.394 AC: 833 AN: 2112

Alfa AF: 0.364 Hom.: 26864

Bravo AF: 0.408

Asia WGS AF: 0.518 AC: 1800 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.6
DANN	Benign	0.45
PhyloP100		-0.051
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: rs4546626; hg19: chr8-110125762;