5-177992760-TG-TGG

Variant names:

• chr5-177992760-T-TG
• rs761018422
• NM_006261.5:c.629dupC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_006261.5(PROP1):​c.629dupC​(p.Pro211ThrfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 243,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P210P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROP1 NM_006261.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: -0.162
• 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Ambry Genetics
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0764 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-177992760-T-TG is Pathogenic according to our data. Variant chr5-177992760-T-TG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 557462.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006261.5. 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
	PROP1	NM_006261.5	MANE Select	c.629dupC	p.Pro211ThrfsTer10	frameshift	Exon 3 of 3	NP_006252.4	O75360

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.629dupC	p.Pro211ThrfsTer10	frameshift	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 28226 Hom.: 0 Cov.: 27

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 1 AN: 243200 Hom.: 0 Cov.: 44 AF XY: 0.00000790 AC XY: 1 AN XY: 126598

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

African (AFR) AF: 0.000134 AC: 1 AN: 7480

American (AMR) AF: 0.00 AC: 0 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5108

East Asian (EAS) AF: 0.00 AC: 0 AN: 8440

South Asian (SAS) AF: 0.00 AC: 0 AN: 26172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 155988

Other (OTH) AF: 0.00 AC: 0 AN: 9282

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 28226 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 13368

African (AFR) AF: 0.00 AC: 0 AN: 6960

American (AMR) AF: 0.00 AC: 0 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 752

East Asian (EAS) AF: 0.00 AC: 0 AN: 920

South Asian (SAS) AF: 0.00 AC: 0 AN: 886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14128

Other (OTH) AF: 0.00 AC: 0 AN: 374

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	1	-	Pituitary hormone deficiency, combined, 2 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=133/67	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: rs761018422; hg19: chr5-177419761;