8-109086403-G-C

Variant names:

• chr8-109086403-G-C
• rs5772
• NM_003301.7:c.-569G>C

Variant summary

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

The NM_003301.7(TRHR):​c.-569G>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 151,996 control chromosomes in the GnomAD database, including 27,354 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 0.60 (27354 hom., cov: 32)
• Consequence: TRHR NM_003301.7 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0100
• Publications: 5 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 (SAS) allele frequency at 95% confidence interval = 0.708 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.-569G>C		upstream_gene	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.-569G>C		upstream_gene	N/A	ENSP00000430711.2

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90783 AN: 151878 Hom.: 27323 Cov.: 32

Gnomad AFR AF: 0.547

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.707

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.569

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.606

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.600

Gnomad OTH AF: 0.620

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

GnomAD4 genome AF: 0.598 AC: 90874 AN: 151996 Hom.: 27354 Cov.: 32 AF XY: 0.604 AC XY: 44852 AN XY: 74290

African (AFR) AF: 0.547 AC: 22668 AN: 41416

American (AMR) AF: 0.708 AC: 10814 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1702 AN: 3470

East Asian (EAS) AF: 0.570 AC: 2947 AN: 5166

South Asian (SAS) AF: 0.728 AC: 3515 AN: 4828

European-Finnish (FIN) AF: 0.606 AC: 6390 AN: 10536

Middle Eastern (MID) AF: 0.486 AC: 142 AN: 292

European-Non Finnish (NFE) AF: 0.600 AC: 40773 AN: 67986

Other (OTH) AF: 0.623 AC: 1316 AN: 2112

Alfa AF: 0.491 Hom.: 1483

Bravo AF: 0.600

Asia WGS AF: 0.676 AC: 2352 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.61
PhyloP100		-0.010
PromoterAI		-0.020	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5772; hg19: chr8-110098632;