chr5-177992760-TG-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_006261.5(PROP1):​c.629delC​(p.Pro210HisfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000247 in 243,182 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: not found (cov: 27)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: PROP1 NM_006261.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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: Pathogenic. The variant received 10 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.
• PP5: Variant 5-177992760-TG-T is Pathogenic according to our data. Variant chr5-177992760-TG-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1523184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.629delC	p.Pro210HisfsTer26	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.629delC	p.Pro210HisfsTer26	frameshift	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.0000247 AC: 3 AN: 121552 AF XY: 0.0000461

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: 0.0000519

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 6 AN: 243182 Hom.: 0 Cov.: 44 AF XY: 0.0000237 AC XY: 3 AN XY: 126592

African (AFR) AF: 0.00 AC: 0 AN: 7480

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

Ashkenazi Jewish (ASJ) AF: 0.000196 AC: 1 AN: 5106

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: 15810

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

European-Non Finnish (NFE) AF: 0.0000192 AC: 3 AN: 155982

Other (OTH) AF: 0.000215 AC: 2 AN: 9282

GnomAD4 genome Cov.: 27

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Pituitary hormone deficiency, combined, 2 (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=32/168	disease causing

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;