3-129977198-A-G

Variant names:

• chr3-129977198-A-G
• rs5663
• NM_007117.5:c.711A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007117.5(TRH):​c.711A>G​(p.Arg237Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.992 in 1,518,612 control chromosomes in the GnomAD database, including 748,233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70552 hom., cov: 31)
  • Exomes 𝑓: 1.0 (677681 hom.)
• Consequence: TRH NM_007117.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.278
• Publications: 12 publications found

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]

LOC124906284 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 3-129977198-A-G is Benign according to our data. Variant chr3-129977198-A-G is described in ClinVar as Benign. ClinVar VariationId is 260117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRH	NM_007117.5	c.711A>G	p.Arg237Arg	synonymous_variant	Exon 3 of 3	ENST00000302649.4	NP_009048.1
LOC124906284		n.129977198A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRH	ENST00000302649.4	c.711A>G	p.Arg237Arg	synonymous_variant	Exon 3 of 3	1	NM_007117.5	ENSP00000303452.3

Frequencies

GnomAD3 genomes AF: 0.961 AC: 146159 AN: 152024 Hom.: 70511 Cov.: 31

Gnomad AFR AF: 0.870

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.981

Gnomad ASJ AF: 0.992

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.990

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.962

GnomAD2 exomes AF: 0.987 AC: 172466 AN: 174756 AF XY: 0.990

Gnomad AFR exome AF: 0.861

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.993

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.994

GnomAD4 exome AF: 0.996 AC: 1360569 AN: 1366470 Hom.: 677681 Cov.: 82 AF XY: 0.996 AC XY: 667058 AN XY: 669676

African (AFR) AF: 0.855 AC: 25828 AN: 30204

American (AMR) AF: 0.990 AC: 28465 AN: 28756

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 19761 AN: 19890

East Asian (EAS) AF: 1.00 AC: 38906 AN: 38906

South Asian (SAS) AF: 1.00 AC: 69514 AN: 69542

European-Finnish (FIN) AF: 1.00 AC: 49684 AN: 49684

Middle Eastern (MID) AF: 0.992 AC: 5032 AN: 5074

European-Non Finnish (NFE) AF: 1.00 AC: 1067793 AN: 1068226

Other (OTH) AF: 0.989 AC: 55586 AN: 56188

GnomAD4 genome AF: 0.961 AC: 146259 AN: 152142 Hom.: 70552 Cov.: 31 AF XY: 0.963 AC XY: 71652 AN XY: 74376

African (AFR) AF: 0.869 AC: 36077 AN: 41496

American (AMR) AF: 0.981 AC: 15007 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.992 AC: 3443 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5101 AN: 5102

South Asian (SAS) AF: 1.00 AC: 4817 AN: 4818

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.990 AC: 289 AN: 292

European-Non Finnish (NFE) AF: 0.999 AC: 67965 AN: 68020

Other (OTH) AF: 0.962 AC: 2032 AN: 2112

Alfa AF: 0.976 Hom.: 34194

Bravo AF: 0.955

Asia WGS AF: 0.990 AC: 3441 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypothalamic hypothyroidism Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	4.5
DANN	Benign	0.41
PhyloP100		-0.28
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5663; hg19: chr3-129696041; COSMIC: COSV108137483;