12-72272831-C-G

Variant names:

• chr12-72272831-C-G
• rs770248867
• NM_013381.3:c.188C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013381.3(TRHDE):​c.188C>G​(p.Pro63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,580,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P63L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TRHDE NM_013381.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.27
• Publications: 0 publications found

Genes affected

TRHDE (HGNC:30748): (thyrotropin releasing hormone degrading enzyme) This gene encodes a member of the peptidase M1 family. The encoded protein is an extracellular peptidase that specifically cleaves and inactivates the neuropeptide thyrotropin-releasing hormone.[provided by RefSeq, Dec 2008]

TRHDE-AS1 (HGNC:27471): (TRHDE antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08974454).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013381.3. 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
	TRHDE	NM_013381.3	MANE Select	c.188C>G	p.Pro63Arg	missense	Exon 1 of 19	NP_037513.2	Q9UKU6
	TRHDE-AS1	NR_026836.1		n.679G>C		non_coding_transcript_exon	Exon 1 of 3
	TRHDE-AS1	NR_026837.1		n.679G>C		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRHDE	ENST00000261180.10	TSL:1 MANE Select	c.188C>G	p.Pro63Arg	missense	Exon 1 of 19	ENSP00000261180.5	Q9UKU6
	TRHDE	ENST00000547300.2	TSL:3	c.188C>G	p.Pro63Arg	missense	Exon 1 of 5	ENSP00000447822.2	A0AA75K8V0
	TRHDE-AS1	ENST00000426250.4	TSL:5	n.1203G>C		non_coding_transcript_exon	Exon 2 of 5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000146 AC: 3 AN: 204920 AF XY: 0.0000177

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000611

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000217

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000147 AC: 21 AN: 1428204 Hom.: 0 Cov.: 33 AF XY: 0.0000141 AC XY: 10 AN XY: 707964

African (AFR) AF: 0.00 AC: 0 AN: 33162

American (AMR) AF: 0.00 AC: 0 AN: 43122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38940

South Asian (SAS) AF: 0.00 AC: 0 AN: 83560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5130

European-Non Finnish (NFE) AF: 0.0000163 AC: 18 AN: 1101630

Other (OTH) AF: 0.0000337 AC: 2 AN: 59346

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000167 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.090
Sift	Benign	0.22	T
Sift4G	Benign	0.97	T
Polyphen		0.047	B
Vest4		0.14
MutPred		0.30		Gain of MoRF binding (P = 0.002)
MVP		0.23
MPC		1.4
ClinPred		0.19	T
GERP RS		3.1
PromoterAI		0.014	Neutral
Varity_R		0.14
gMVP		0.51
Mutation Taster		=81/19	polymorphism

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: rs770248867; hg19: chr12-72666611;