chr5-177994323-GGTGGAGCACTCGA-G

Variant names:

• chr5-177994323-GGTGGAGCACTCGA-G
• rs587776682
• NM_006261.5:c.112_124delTCGAGTGCTCCAC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_006261.5(PROP1):​c.112_124delTCGAGTGCTCCAC​(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. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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. Variant results in nonsense mediated mRNA decay.

• 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• pituitary hormone deficiency, combined, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• panhypopituitarism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-177994323-GGTGGAGCACTCGA-G is Pathogenic according to our data. Variant chr5-177994323-GGTGGAGCACTCGA-G is described in CliVar as Pathogenic. Clinvar id is 8101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177994323-GGTGGAGCACTCGA-G is described in CliVar 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 rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.112_124delTCGAGTGCTCCAC	p.Ser38ProfsTer123	frameshift_variant, splice_region_variant	Exon 2 of 3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.112_124delTCGAGTGCTCCAC	p.Ser38ProfsTer123	frameshift_variant, splice_region_variant	Exon 2 of 3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225024 AF XY: 0.00

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 42396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25766

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106208

Other (OTH) AF: 0.00 AC: 0 AN: 59958

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000016), which strongly suggests a high chance of mosaicism in these individuals.

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

Oct 05, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Possible founder variant on Indian subcontinent [Turton et al 2005] -

Oct 31, 2013

Endocrinology Clinic, Seth G.S. Medical College

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Aug 03, 2016

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:1

Nov 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=85/115	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs587776682; hg19: chr5-177421324;