rs5658

Positions:

• chr3-129975838-C-G

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.22C>G​(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 1,608,952 control chromosomes in the GnomAD database, including 13,151 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.15 (2354 hom., cov: 33)
  • Exomes 𝑓: 0.10 (10797 hom.)
• Consequence: TRH ENST00000302649.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.87

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=0.005417675).
• BP6: Variant 3-129975838-C-G is Benign according to our data. Variant chr3-129975838-C-G is described in ClinVar as [Benign]. Clinvar id is 260114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-129975838-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.323 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRH	NM_007117.5	c.22C>G	p.Leu8Val	missense_variant	2/3	ENST00000302649.4	NP_009048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4	c.22C>G	p.Leu8Val	missense_variant	2/3	1	NM_007117.5	ENSP00000303452	P2
TRH	ENST00000507066.1	c.22C>G	p.Leu8Val	missense_variant	2/3	5		ENSP00000426522	A1

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22871 AN: 152176 Hom.: 2348 Cov.: 33

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.0772

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0807

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.154 AC: 36936 AN: 239362 Hom.: 3957 AF XY: 0.146 AC XY: 19070 AN XY: 130806

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.313

Gnomad ASJ exome AF: 0.0850

Gnomad EAS exome AF: 0.328

Gnomad SAS exome AF: 0.159

Gnomad FIN exome AF: 0.0924

Gnomad NFE exome AF: 0.0836

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.104 AC: 151319 AN: 1456658 Hom.: 10797 Cov.: 33 AF XY: 0.104 AC XY: 75162 AN XY: 724452

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.307

Gnomad4 ASJ exome AF: 0.0835

Gnomad4 EAS exome AF: 0.330

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.0931

Gnomad4 NFE exome AF: 0.0803

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.150 AC: 22918 AN: 152294 Hom.: 2354 Cov.: 33 AF XY: 0.156 AC XY: 11594 AN XY: 74466

Gnomad4 AFR AF: 0.222

Gnomad4 AMR AF: 0.268

Gnomad4 ASJ AF: 0.0772

Gnomad4 EAS AF: 0.336

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.0837

Gnomad4 NFE AF: 0.0807

Gnomad4 OTH AF: 0.156

Alfa AF: 0.0974 Hom.: 282

Bravo AF: 0.166

TwinsUK AF: 0.0823 AC: 305

ALSPAC AF: 0.0864 AC: 333

ESP6500AA AF: 0.203 AC: 869

ESP6500EA AF: 0.0796 AC: 669

ExAC AF: 0.143 AC: 17278

Asia WGS AF: 0.274 AC: 951 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	0.89	P;P
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.040
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.76	P;.
Vest4		0.17
MPC		0.42
ClinPred		0.014	T
GERP RS		2.2
Varity_R		0.10
gMVP		0.37

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: rs5658; hg19: chr3-129694681; COSMIC: COSV57014675;