3-129976735-G-A

Position:

• chr3-129976735-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000302649.4(TRH):​c.248G>A​(p.Arg83His) variant causes a missense change. The variant allele was found at a frequency of 0.00199 in 1,613,804 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (22 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (23 hom.)
• Consequence: TRH ENST00000302649.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.04

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 (MetaRNN=0.01296562).
• BP6: Variant 3-129976735-G-A is Benign according to our data. Variant chr3-129976735-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129976735-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00923 (1403/152052) while in subpopulation AFR AF= 0.0298 (1235/41454). AF 95% confidence interval is 0.0284. There are 22 homozygotes in gnomad4. There are 642 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRH	NM_007117.5	c.248G>A	p.Arg83His	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.248G>A	p.Arg83His	missense_variant	3/3	1	NM_007117.5	ENSP00000303452	P2
TRH	ENST00000507066.1	c.236G>A	p.Arg79His	missense_variant	3/3	5		ENSP00000426522	A1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 1398 AN: 151934 Hom.: 22 Cov.: 31

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00728

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00270 AC: 678 AN: 251276 Hom.: 8 AF XY: 0.00237 AC XY: 322 AN XY: 135804

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000352

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00124 AC: 1811 AN: 1461752 Hom.: 23 Cov.: 94 AF XY: 0.00115 AC XY: 836 AN XY: 727170

Gnomad4 AFR exome AF: 0.0319

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000545

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000241

Gnomad4 OTH exome AF: 0.00334

GnomAD4 genome AF: 0.00923 AC: 1403 AN: 152052 Hom.: 22 Cov.: 31 AF XY: 0.00864 AC XY: 642 AN XY: 74336

Gnomad4 AFR AF: 0.0298

Gnomad4 AMR AF: 0.00720

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00145 Hom.: 3

Bravo AF: 0.0109

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0309 AC: 136

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00323 AC: 392

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000652

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 20, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 20, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.67
MVP		0.91
MPC		0.52
ClinPred		0.028	T
GERP RS		5.0
Varity_R		0.69
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs61740106; hg19: chr3-129695578;