rs1135320

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006261.5(PROP1):c.27T>C(p.Ala9Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,148 control chromosomes in the GnomAD database, including 168,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14007 hom., cov: 32)

Exomes 𝑓: 0.46 ( 154290 hom. )

Consequence

PROP1
NM_006261.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -2.04

Publications

16 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: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BP6

Variant 5-177995907-A-G is Benign according to our data. Variant chr5-177995907-A-G is described in ClinVar as Benign. ClinVar VariationId is 353017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROP1	NM_006261.5 link	c.27T>C	p.Ala9Ala	synonymous_variant	Exon 1 of 3	ENST00000308304.2	NP_006252.4	O75360A0A0G2JQ02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2 link	c.27T>C	p.Ala9Ala	synonymous_variant	Exon 1 of 3	1	NM_006261.5	ENSP00000311290.2		O75360

Frequencies

GnomAD3 genomes

AF:

0.418

AC:

63531

AN:

151834

Hom.:

13996

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.501

Gnomad AMR

AF:

0.508

Gnomad ASJ

AF:

0.526

Gnomad EAS

AF:

0.568

Gnomad SAS

AF:

0.578

Gnomad FIN

AF:

0.490

Gnomad MID

AF:

0.599

Gnomad NFE

AF:

0.439

Gnomad OTH

AF:

0.467

GnomAD2 exomes

AF:

0.483

AC:

121262

AN:

251114

AF XY:

0.489

show subpopulations

Gnomad AFR exome

AF:

0.276

Gnomad AMR exome

AF:

0.556

Gnomad ASJ exome

AF:

0.525

Gnomad EAS exome

AF:

0.577

Gnomad FIN exome

AF:

0.485

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.479

GnomAD4 exome

AF:

0.455

AC:

665221

AN:

1461196

Hom.:

154290

Cov.:

AF XY:

0.459

AC XY:

334033

AN XY:

726966

show subpopulations

African (AFR)

AF:

0.279

AC:

9333

AN:

33476

American (AMR)

AF:

0.550

AC:

24603

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

13734

AN:

26130

East Asian (EAS)

AF:

0.622

AC:

24695

AN:

39698

South Asian (SAS)

AF:

0.577

AC:

49743

AN:

86254

European-Finnish (FIN)

AF:

0.483

AC:

25646

AN:

53144

Middle Eastern (MID)

AF:

0.588

AC:

3392

AN:

5768

European-Non Finnish (NFE)

AF:

0.438

AC:

486353

AN:

1111638

Other (OTH)

AF:

0.459

AC:

27722

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

19861

39722

59583

79444

99305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14868

29736

44604

59472

74340

<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

AF:

0.418

AC:

63579

AN:

151952

Hom.:

14007

Cov.:

AF XY:

0.426

AC XY:

31626

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.282

AC:

11670

AN:

41442

American (AMR)

AF:

0.508

AC:

7764

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

1826

AN:

3470

East Asian (EAS)

AF:

0.568

AC:

2913

AN:

5128

South Asian (SAS)

AF:

0.581

AC:

2796

AN:

4814

European-Finnish (FIN)

AF:

0.490

AC:

5167

AN:

10554

Middle Eastern (MID)

AF:

0.606

AC:

177

AN:

292

European-Non Finnish (NFE)

AF:

0.439

AC:

29818

AN:

67954

Other (OTH)

AF:

0.470

AC:

993

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1858

3717

5575

7434

9292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<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:

0.431

Hom.:

26425

Bravo

AF:

0.417

Asia WGS

AF:

0.552

AC:

1916

AN:

3478

EpiCase

AF:

0.463

EpiControl

AF:

0.459

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pituitary hormone deficiency, combined, 2

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 25, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:3

Jul 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

2.6

(source)

DANN

Benign

0.14

PhyloP100

-2.0

PromoterAI

0.059

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over