rs2233787

Variant names:

• chr5-177992657-C-T
• rs2233787
• NM_006261.5:c.*52G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006261.5(PROP1):​c.*52G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,315,538 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (14 hom., cov: 29)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: PROP1 NM_006261.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.11
• 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), Myriad Women’s Health, G2P, 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-177992657-C-T is Benign according to our data. Variant chr5-177992657-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353011.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00865 (1292/149310) while in subpopulation NFE AF = 0.0121 (820/67738). AF 95% confidence interval is 0.0114. There are 14 homozygotes in GnomAd4. There are 627 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,AD gene

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.*52G>A		3_prime_UTR	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.*52G>A		3_prime_UTR	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1292 AN: 149208 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0651

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.0220

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.00765

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.0104 AC: 12148 AN: 1166228 Hom.: 90 Cov.: 16 AF XY: 0.0102 AC XY: 6000 AN XY: 585512

African (AFR) AF: 0.00141 AC: 39 AN: 27626

American (AMR) AF: 0.00846 AC: 283 AN: 33454

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 637 AN: 22798

East Asian (EAS) AF: 0.00 AC: 0 AN: 36304

South Asian (SAS) AF: 0.00126 AC: 93 AN: 73754

European-Finnish (FIN) AF: 0.0107 AC: 382 AN: 35582

Middle Eastern (MID) AF: 0.0151 AC: 54 AN: 3580

European-Non Finnish (NFE) AF: 0.0115 AC: 10144 AN: 882592

Other (OTH) AF: 0.0102 AC: 516 AN: 50538

GnomAD4 genome AF: 0.00865 AC: 1292 AN: 149310 Hom.: 14 Cov.: 29 AF XY: 0.00864 AC XY: 627 AN XY: 72590

African (AFR) AF: 0.00212 AC: 86 AN: 40638

American (AMR) AF: 0.00979 AC: 141 AN: 14396

Ashkenazi Jewish (ASJ) AF: 0.0220 AC: 76 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5006

South Asian (SAS) AF: 0.00189 AC: 9 AN: 4750

European-Finnish (FIN) AF: 0.00765 AC: 77 AN: 10064

Middle Eastern (MID) AF: 0.00709 AC: 2 AN: 282

European-Non Finnish (NFE) AF: 0.0121 AC: 820 AN: 67738

Other (OTH) AF: 0.0106 AC: 22 AN: 2072

Alfa AF: 0.00969 Hom.: 4

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.87
DANN	Benign	0.41
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs2233787; hg19: chr5-177419658;