rs121917843

Positions:

• chr5-177994231-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000308304.2(PROP1):​c.217C>T​(p.Arg73Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000752 in 1,461,800 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PROP1 ENST00000308304.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.63

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PROP1_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in ENST00000308304.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-177994230-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 5-177994231-G-A is Pathogenic according to our data. Variant chr5-177994231-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 8104.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	c.217C>T	p.Arg73Cys	missense_variant	2/3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.217C>T	p.Arg73Cys	missense_variant	2/3	1	NM_006261.5	ENSP00000311290	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251102 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 11, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 08, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 09, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 73 of the PROP1 protein (p.Arg73Cys). This variant is present in population databases (rs121917843, gnomAD 0.004%). This missense change has been observed in individuals with combined pituitary hormone deficiency (PMID: 9824293, 10946881, 11549703, 15531542, 25557026). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8104). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROP1 protein function. Experimental studies have shown that this missense change affects PROP1 function (PMID: 15531542, 25557026). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Benign	0.59	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.9	H
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MutPred		0.96		Loss of MoRF binding (P = 0.0099);
MVP		0.97
MPC		0.58
ClinPred		1.0	D
GERP RS		2.5
Varity_R		0.79
gMVP		0.81

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: rs121917843; hg19: chr5-177421232;