3-129976695-C-T

Position:

• chr3-129976695-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000302649.4(TRH):​c.212-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,608,728 control chromosomes in the GnomAD database, including 792,576 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70530 hom., cov: 30)
  • Exomes 𝑓: 1.0 (722046 hom.)
• Consequence: TRH ENST00000302649.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001045
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.108

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-129976695-C-T is Benign according to our data. Variant chr3-129976695-C-T is described in ClinVar as [Benign]. Clinvar id is 260113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129976695-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRH	NM_007117.5	c.212-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000302649.4	NP_009048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4	c.212-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_007117.5	ENSP00000303452	P2
TRH	ENST00000507066.1	c.200-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000426522	A1

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146127 AN: 151996 Hom.: 70488 Cov.: 30

Gnomad AFR AF: 0.870

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.981

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 0.998

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.962

GnomAD3 exomes AF: 0.989 AC: 246658 AN: 249388 Hom.: 122116 AF XY: 0.991 AC XY: 133692 AN XY: 134850

Gnomad AFR exome AF: 0.863

Gnomad AMR exome AF: 0.993

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.997

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.993

GnomAD4 exome AF: 0.995 AC: 1449981 AN: 1456614 Hom.: 722046 Cov.: 68 AF XY: 0.996 AC XY: 721072 AN XY: 723994

Gnomad4 AFR exome AF: 0.856

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.994

Gnomad4 EAS exome AF: 0.998

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.988

GnomAD4 genome AF: 0.961 AC: 146228 AN: 152114 Hom.: 70530 Cov.: 30 AF XY: 0.963 AC XY: 71626 AN XY: 74362

Gnomad4 AFR AF: 0.869

Gnomad4 AMR AF: 0.981

Gnomad4 ASJ AF: 0.992

Gnomad4 EAS AF: 0.998

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.962

Alfa AF: 0.983 Hom.: 47111

Bravo AF: 0.955

Asia WGS AF: 0.988 AC: 3437 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2020	- -

Hypothalamic hypothyroidism Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.1
DANN	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0020
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: rs784704; hg19: chr3-129695538;