5-177994296-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS1

The NM_006261.5(PROP1):c.152G>T(p.Gly51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51A) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

PROP1
NM_006261.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

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 -7 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=0.009972423).

BP6

Variant 5-177994296-C-A is Benign according to our data. Variant chr5-177994296-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 742937.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000092 (14/152232) while in subpopulation EAS AF = 0.00174 (9/5166). AF 95% confidence interval is 0.000909. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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>T	p.Gly51Val	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>T	p.Gly51Val	missense	Exon 2 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00174

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000222

AC:

AN:

243052

AF XY:

0.000227

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00215

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000739

Gnomad OTH exome

AF:

0.000505

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1459246

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

725598

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33442

American (AMR)

AF:

0.0000451

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26044

East Asian (EAS)

AF:

0.00121

AC:

AN:

39616

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86096

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000234

AC:

AN:

1110404

Other (OTH)

AF:

0.0000830

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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

AF:

0.0000920

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41540

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5166

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

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:

0.00000877

Hom.:

ExAC

AF:

0.000223

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (1)

Pituitary hormone deficiency, combined, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

0.011

(source)

DANN

Benign

0.16

DEOGEN2

Benign

0.088

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.00089

LIST_S2

Benign

0.23

M_CAP

Benign

0.055

MetaRNN

Benign

0.010

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-1.2

PhyloP100

-0.86

PrimateAI

Benign

0.47

PROVEAN

Benign

1.2

REVEL

Benign

0.17

Sift

Benign

0.58

Sift4G

Benign

0.20

Polyphen

0.0

Vest4

0.12

MutPred

0.32

Loss of methylation at R53 (P = 0.0557)

MVP

0.63

MPC

0.12

ClinPred

0.0065

GERP RS

-4.4

Varity_R

0.026

gMVP

0.52

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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