rs794726694

Positions:

• chr5-177994323-GGTGGAGCACTCGA-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006261.5(PROP1):​c.112_124del​(p.Ser38ProfsTer123) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,450,900 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S38S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (1 hom.)
• Consequence: PROP1 NM_006261.5 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 2.78

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.

• 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 29 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177994323-GGTGGAGCACTCGA-G is Pathogenic according to our data. Variant chr5-177994323-GGTGGAGCACTCGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 8101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROP1	NM_006261.5	c.112_124del	p.Ser38ProfsTer123	frameshift_variant, splice_region_variant	2/3	ENST00000308304.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROP1	ENST00000308304.2	c.112_124del	p.Ser38ProfsTer123	frameshift_variant, splice_region_variant	2/3	1	NM_006261.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000444 AC: 1 AN: 225024 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122260

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: 0.0000344

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 10 AN: 1450900 Hom.: 1 AF XY: 0.0000111 AC XY: 8 AN XY: 720680

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: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 05, 2023	- -
Likely pathogenic, no assertion criteria provided	case-control	Endocrinology Clinic, Seth G.S. Medical College	Oct 31, 2013	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2000	- -
not provided, no classification provided	literature only	GeneReviews	-	Possible founder variant on Indian subcontinent [Turton et al 2005] -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 03, 2016	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

This sequence change creates a premature translational stop signal (p.Ser38Profs*123) in the PROP1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 189 amino acid(s) of the PROP1 protein. This variant is present in population databases (rs587776682, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with pituitary hormone deficiency (PMID: 11134108, 15963055). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8101). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs587776682; hg19: chr5-177421324;