Genetic Variant PROP1:p.Pro212Pro (chr5-177992754-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_006261.5(PROP1):c.636T>C(p.Pro212Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P212P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.014 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00055 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PROP1
NM_006261.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.371

Publications

0 publications found

Variant links:

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

PROP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 5-177992754-A-G is Benign according to our data. Variant chr5-177992754-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284436.

BP7

Synonymous conserved (PhyloP=-0.371 with no splicing effect.

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.636T>C	p.Pro212Pro	synonymous	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.636T>C	p.Pro212Pro	synonymous	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

261

AN:

18130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0183

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00768

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.00976

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0340

GnomAD2 exomes

AF:

0.00100

AC:

129

AN:

129002

AF XY:

0.00116

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000151

Gnomad ASJ exome

AF:

0.00143

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000553

Gnomad NFE exome

AF:

0.00167

Gnomad OTH exome

AF:

0.00146

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000553

AC:

162

AN:

292780

Hom.:

Cov.:

AF XY:

0.000636

AC XY:

AN XY:

150884

show subpopulations

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

African (AFR)

AF:

0.000122

AC:

AN:

8184

American (AMR)

AF:

0.000407

AC:

AN:

14736

Ashkenazi Jewish (ASJ)

AF:

0.00119

AC:

AN:

5894

East Asian (EAS)

AF:

0.00

AC:

AN:

9928

South Asian (SAS)

AF:

0.000307

AC:

AN:

29272

European-Finnish (FIN)

AF:

0.000596

AC:

AN:

16770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

804

European-Non Finnish (NFE)

AF:

0.000638

AC:

125

AN:

195808

Other (OTH)

AF:

0.000351

AC:

AN:

11384

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.272

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0143

AC:

260

AN:

18170

Hom.:

Cov.:

AF XY:

0.0145

AC XY:

128

AN XY:

8826

show subpopulations

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

African (AFR)

AF:

0.0181

AC:

AN:

4254

American (AMR)

AF:

0.00766

AC:

AN:

1566

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

520

East Asian (EAS)

AF:

0.00135

AC:

AN:

740

South Asian (SAS)

AF:

0.0146

AC:

AN:

478

European-Finnish (FIN)

AF:

0.00976

AC:

AN:

922

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0148

AC:

137

AN:

9258

Other (OTH)

AF:

0.0333

AC:

AN:

300

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.6

(source)

DANN

Benign

0.55

PhyloP100

-0.37

Mutation Taster

=100/0

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over