Variant rs786204604 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The ENST00000308304.2(PROP1):c.334C>T(p.Arg112Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R112R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PROP1
ENST00000308304.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.04

Variant links:

Genes affected

PROP1 (HGNC:9455): (PROP paired-like homeobox 1) This gene encodes a paired-like homeodomain transcription factor in the developing pituitary gland. Expression occurs prior to and is required for expression of pou domain transcription factor 1, which is responsible for pituitary development and hormone expression. Mutations in this gene have been associated with combined pituitary hormone deficiency-2 as well as deficiencies in luteinizing hormone, follicle-stimulating hormone, growth hormone, prolactin, and thyroid-stimulating hormone. [provided by RefSeq, Sep 2011]

PROP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-177994114-G-A is Pathogenic according to our data. Variant chr5-177994114-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROP1	NM_006261.5 linkuse as main transcript	c.334C>T	p.Arg112Ter	stop_gained	2/3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2 linkuse as main transcript	c.334C>T	p.Arg112Ter	stop_gained	2/3	1	NM_006261.5	ENSP00000311290	P1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461546

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000330

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pituitary hormone deficiency, combined, 2

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Sep 25, 2014	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 11, 2017	The PROP1 c.334C>T (p.Arg112Ter) stop-gained variant has been reported in two studies and is found in a total of three individuals, including one in a homozygous state and two in a compound heterozygous state. The homozygote is a Japanese individual with combined pituitary hormone deficiency (CDPH) (Ogo et al. 2011). The compound heterozygotes are two brothers with ages of onset of four and six; they are reported to present with a milder phenotype of CDPH, whereby central hypothyroidism was the first noted symptom (Ziemnicka et al. 2015). The p.Arg112Ter variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. The variant is in a region of good sequence coverage, so the variant is presumed to be rare. In silico prediction tools suggest that the variant disrupts the paired-like homeodomain that is required for DNA interaction with the PROP1 protein, leading to loss of DNA binding activity, although other studies suggest the protein maintains some functionality (Ziemnicka et al. 2015). Based on the evidence and the potential impact of stop-gained variants, the p.Arg112Ter variant is classified as likely pathogenic for combined pituitary hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 21, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change creates a premature translational stop signal (p.Arg112*) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 115 amino acid(s) of the PROP1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with combined pituitary hormone deficiency (PMID: 22111336, 26608600). ClinVar contains an entry for this variant (Variation ID: 188982). This variant disrupts a region of the PROP1 protein in which other variant(s) (p.Ser156Phefs*37) have been determined to be pathogenic (PMID: 16759034, 20381582). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.60

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.20

Eigen_PC

Benign

-0.039

FATHMM_MKL

Benign

0.45

MutationTaster

Benign

1.0

Vest4

0.66

GERP RS

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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