rs5660

Variant names:

• chr3-129976871-T-C
• rs5660
• NM_007117.5:c.384T>C

Your query was ambiguous. Multiple possible variants found:

• chr3-129976871-T-C
• chr3-129976871-T-A

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.384T>C​(p.Asp128Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0697 in 1,612,116 control chromosomes in the GnomAD database, including 4,432 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (445 hom., cov: 30)
  • Exomes 𝑓: 0.070 (3987 hom.)
• Consequence: TRH NM_007117.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.978
• Publications: 8 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=-0.9).
• BP6: Variant 3-129976871-T-C is Benign according to our data. Variant chr3-129976871-T-C is described in ClinVar as Benign. ClinVar VariationId is 260115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.978 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0973 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007117.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRH	NM_007117.5	MANE Select	c.384T>C	p.Asp128Asp	synonymous	Exon 3 of 3	NP_009048.1	P20396

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRH	ENST00000302649.4	TSL:1 MANE Select	c.384T>C	p.Asp128Asp	synonymous	Exon 3 of 3	ENSP00000303452.3	P20396
	TRH	ENST00000507066.1	TSL:5	c.372T>C	p.Asp124Asp	synonymous	Exon 3 of 3	ENSP00000426522.1	D6RFM1
	ENSG00000250643	ENST00000785099.1		n.298-4763A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0717 AC: 10755 AN: 150098 Hom.: 445 Cov.: 30

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00221

Gnomad AMR AF: 0.0682

Gnomad ASJ AF: 0.0573

Gnomad EAS AF: 0.00240

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.0432

Gnomad MID AF: 0.0517

Gnomad NFE AF: 0.0702

Gnomad OTH AF: 0.0802

GnomAD2 exomes AF: 0.0547 AC: 13756 AN: 251414 AF XY: 0.0540

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.0473

Gnomad ASJ exome AF: 0.0583

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.0406

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.0645

GnomAD4 exome AF: 0.0695 AC: 101641 AN: 1461892 Hom.: 3987 Cov.: 98 AF XY: 0.0680 AC XY: 49427 AN XY: 727246

African (AFR) AF: 0.0998 AC: 3342 AN: 33480

American (AMR) AF: 0.0506 AC: 2264 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0568 AC: 1485 AN: 26136

East Asian (EAS) AF: 0.00174 AC: 69 AN: 39700

South Asian (SAS) AF: 0.0191 AC: 1649 AN: 86258

European-Finnish (FIN) AF: 0.0422 AC: 2254 AN: 53418

Middle Eastern (MID) AF: 0.0482 AC: 278 AN: 5768

European-Non Finnish (NFE) AF: 0.0775 AC: 86176 AN: 1112012

Other (OTH) AF: 0.0683 AC: 4124 AN: 60396

GnomAD4 genome AF: 0.0716 AC: 10762 AN: 150224 Hom.: 445 Cov.: 30 AF XY: 0.0691 AC XY: 5065 AN XY: 73296

African (AFR) AF: 0.0998 AC: 4070 AN: 40764

American (AMR) AF: 0.0681 AC: 1031 AN: 15130

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 198 AN: 3454

East Asian (EAS) AF: 0.00261 AC: 13 AN: 4984

South Asian (SAS) AF: 0.0172 AC: 81 AN: 4712

European-Finnish (FIN) AF: 0.0432 AC: 449 AN: 10390

Middle Eastern (MID) AF: 0.0515 AC: 14 AN: 272

European-Non Finnish (NFE) AF: 0.0702 AC: 4739 AN: 67532

Other (OTH) AF: 0.0793 AC: 165 AN: 2082

Alfa AF: 0.0697 Hom.: 407

Bravo AF: 0.0754

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0775

EpiControl AF: 0.0809

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.53
DANN	Benign	0.35
PhyloP100		-0.98
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: rs5660; hg19: chr3-129695714; COSMIC: COSV57014970;