3-129977050-C-T

Position:

• chr3-129977050-C-T

Variant summary

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

The ENST00000302649.4(TRH):​c.563C>T​(p.Pro188Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00176 in 1,611,080 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (13 hom.)
• Consequence: TRH ENST00000302649.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.39

Genes affected

TRH (HGNC:12298): (thyrotropin releasing hormone) This gene encodes a member of the thyrotropin-releasing hormone family. Cleavage of the encoded proprotein releases mature thyrotropin-releasing hormone, which is a tripeptide hypothalamic regulatory hormone. The human proprotein contains six thyrotropin-releasing hormone tripeptides. Thyrotropin-releasing hormone is involved in the regulation and release of thyroid-stimulating hormone, as well as prolactin. Deficiency of this hormone has been associated with hypothalamic hypothyroidism. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.019107252).
• BP6: Variant 3-129977050-C-T is Benign according to our data. Variant chr3-129977050-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 771857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129977050-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRH	NM_007117.5	c.563C>T	p.Pro188Leu	missense_variant	3/3	ENST00000302649.4	NP_009048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4	c.563C>T	p.Pro188Leu	missense_variant	3/3	1	NM_007117.5	ENSP00000303452	P2
TRH	ENST00000507066.1	c.551C>T	p.Pro184Leu	missense_variant	3/3	5		ENSP00000426522	A1

Frequencies

GnomAD3 genomes AF: 0.00399 AC: 606 AN: 152060 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00116

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00280 AC: 697 AN: 248566 Hom.: 6 AF XY: 0.00273 AC XY: 369 AN XY: 134934

Gnomad AFR exome AF: 0.00868

Gnomad AMR exome AF: 0.00412

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00153 AC: 2228 AN: 1458902 Hom.: 13 Cov.: 97 AF XY: 0.00147 AC XY: 1066 AN XY: 725196

Gnomad4 AFR exome AF: 0.00821

Gnomad4 AMR exome AF: 0.00442

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000808

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.00398 AC: 606 AN: 152178 Hom.: 2 Cov.: 31 AF XY: 0.00438 AC XY: 326 AN XY: 74386

Gnomad4 AFR AF: 0.00782

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00116

Gnomad4 OTH AF: 0.00615

Alfa AF: 0.00337 Hom.: 4

Bravo AF: 0.00443

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TRH: BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 04, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.019	T;T
MetaSVM	Uncertain	0.013	D
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-8.9	D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.041	D;D
Polyphen		1.0	D;.
Vest4		0.56
MVP		0.93
MPC		0.47
ClinPred		0.086	T
GERP RS		3.8
Varity_R		0.81
gMVP		0.26

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: rs35004321; hg19: chr3-129695893;