5-177992760-TG-TGGGGGGGGGGG

Variant names:

• chr5-177992760-T-TGGGGGGGGGG
• rs761018422
• NM_006261.5:c.629_630insCCCCCCCCCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_006261.5(PROP1):​c.629_630insCCCCCCCCCC​(p.Met214ThrfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROP1 NM_006261.5 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• 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: Uncertain_significance. The variant received 2 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.

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.629_630insCCCCCCCCCC	p.Met214ThrfsTer10	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.629_630insCCCCCCCCCC	p.Met214ThrfsTer10	frameshift	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 28212 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 243088 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 126554

African (AFR) AF: 0.00 AC: 0 AN: 7476

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5102

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 26170

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: 155892

Other (OTH) AF: 0.00 AC: 0 AN: 9278

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 28252 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 13408

African (AFR) AF: 0.00 AC: 0 AN: 6988

American (AMR) AF: 0.00 AC: 0 AN: 2504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 750

East Asian (EAS) AF: 0.00 AC: 0 AN: 918

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: 52

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14120

Other (OTH) AF: 0.00 AC: 0 AN: 380

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.16
Mutation Taster		=148/52	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs761018422; hg19: chr5-177419761;