rs1554182368

Variant names:

• chr5-177992778-GC-G
• rs1554182368
• NM_006261.5:c.611delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_006261.5(PROP1):​c.611delG​(p.Gly204AlafsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000485 in 1,442,468 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: PROP1 NM_006261.5 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: -0.0770
• Publications: 0 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 12 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. There are 7 pathogenic variants in the truncated region.
• PP5: Variant 5-177992778-GC-G is Pathogenic according to our data. Variant chr5-177992778-GC-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 557824.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.611delG	p.Gly204AlafsTer32	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.611delG	p.Gly204AlafsTer32	frameshift	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000485 AC: 7 AN: 1442468 Hom.: 0 Cov.: 40 AF XY: 0.00000140 AC XY: 1 AN XY: 714908

African (AFR) AF: 0.00 AC: 0 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 43240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.00 AC: 0 AN: 83438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4326

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1103054

Other (OTH) AF: 0.0000168 AC: 1 AN: 59482

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.077

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: rs1554182368; hg19: chr5-177419779;