NM_006261.5:c.152G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_006261.5(PROP1):c.152G>C(p.Gly51Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,611,454 control chromosomes in the GnomAD database, including 422 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 189 hom., cov: 31)

Exomes 𝑓: 0.0032 ( 233 hom. )

Consequence

PROP1
NM_006261.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.859

Publications

7 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), 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

PROP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a chain Homeobox protein prophet of Pit-1 (size 225) in uniprot entity PROP1_HUMAN there are 38 pathogenic changes around while only 8 benign (83%) in NM_006261.5

BP4

Computational evidence support a benign effect (MetaRNN=0.0019489825).

BP6

Variant 5-177994296-C-G is Benign according to our data. Variant chr5-177994296-C-G is described in ClinVar as Benign. ClinVar VariationId is 188820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 is higher than 0.05.

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.152G>C	p.Gly51Ala	missense	Exon 2 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.152G>C	p.Gly51Ala	missense	Exon 2 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes

AF:

0.0285

AC:

4340

AN:

152098

Hom.:

189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0995

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00825

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00764

AC:

1857

AN:

243052

AF XY:

0.00551

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.00477

Gnomad ASJ exome

AF:

0.000711

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.000480

Gnomad OTH exome

AF:

0.00387

GnomAD4 exome

AF:

0.00319

AC:

4653

AN:

1459238

Hom.:

233

Cov.:

AF XY:

0.00276

AC XY:

2001

AN XY:

725594

show subpopulations

African (AFR)

AF:

0.107

AC:

3564

AN:

33436

American (AMR)

AF:

0.00505

AC:

224

AN:

44348

Ashkenazi Jewish (ASJ)

AF:

0.000499

AC:

AN:

26044

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39616

South Asian (SAS)

AF:

0.000511

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.000300

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00417

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000344

AC:

382

AN:

1110404

Other (OTH)

AF:

0.00639

AC:

385

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

254

508

761

1015

1269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

232

348

464

580

<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:

0.0286

AC:

4353

AN:

152216

Hom.:

189

Cov.:

AF XY:

0.0272

AC XY:

2021

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0996

AC:

4134

AN:

41524

American (AMR)

AF:

0.00824

AC:

126

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.000194

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68000

Other (OTH)

AF:

0.0156

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.00178

Hom.:

Bravo

AF:

0.0330

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0971

AC:

427

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00948

AC:

1150

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Pituitary hormone deficiency, combined, 2 (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.010

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.081

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.00078

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0019

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

PhyloP100

-0.86

PrimateAI

Benign

0.47

PROVEAN

Benign

1.2

REVEL

Benign

0.15

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.11

MVP

0.64

MPC

0.10

ClinPred

0.00042

GERP RS

-4.4

Varity_R

0.023

gMVP

0.57

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over