rs1800197

Positions:

chr5-177992966-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006261.5(PROP1):c.424G>A(p.Ala142Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,613,028 control chromosomes in the GnomAD database, including 61,687 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. A142V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.23 ( 4323 hom., cov: 30)

Exomes 𝑓: 0.28 ( 57364 hom. )

Consequence

PROP1
NM_006261.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.439

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004379958).

BP6

Variant 5-177992966-C-T is Benign according to our data. Variant chr5-177992966-C-T is described in ClinVar as [Benign]. Clinvar id is 196434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177992966-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROP1	NM_006261.5 linkuse as main transcript	c.424G>A	p.Ala142Thr	missense_variant	3/3	ENST00000308304.2	NP_006252.4	O75360A0A0G2JQ02

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2 linkuse as main transcript	c.424G>A	p.Ala142Thr	missense_variant	3/3	1	NM_006261.5	ENSP00000311290.2		O75360

Frequencies

GnomAD3 genomes

AF:

0.227

AC:

34381

AN:

151696

Hom.:

4324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.237

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.0834

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.198

Gnomad MID

AF:

0.223

Gnomad NFE

AF:

0.285

Gnomad OTH

AF:

0.225

GnomAD3 exomes

AF:

0.248

AC:

62009

AN:

250184

Hom.:

8083

AF XY:

0.250

AC XY:

33816

AN XY:

135212

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.301

Gnomad ASJ exome

AF:

0.244

Gnomad EAS exome

AF:

0.0790

Gnomad SAS exome

AF:

0.249

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.284

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.276

AC:

403393

AN:

1461214

Hom.:

57364

Cov.:

AF XY:

0.275

AC XY:

199803

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.299

Gnomad4 ASJ exome

AF:

0.241

Gnomad4 EAS exome

AF:

0.0825

Gnomad4 SAS exome

AF:

0.246

Gnomad4 FIN exome

AF:

0.215

Gnomad4 NFE exome

AF:

0.294

Gnomad4 OTH exome

AF:

0.262

GnomAD4 genome

AF:

0.227

AC:

34391

AN:

151814

Hom.:

4323

Cov.:

AF XY:

0.224

AC XY:

16637

AN XY:

74152

show subpopulations

Gnomad4 AFR

AF:

0.133

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.237

Gnomad4 EAS

AF:

0.0838

Gnomad4 SAS

AF:

0.241

Gnomad4 FIN

AF:

0.198

Gnomad4 NFE

AF:

0.285

Gnomad4 OTH

AF:

0.223

Alfa

AF:

0.271

Hom.:

14138

Bravo

AF:

0.226

TwinsUK

AF:

0.298

AC:

1105

ALSPAC

AF:

0.306

AC:

1181

ESP6500AA

AF:

0.130

AC:

574

ESP6500EA

AF:

0.293

AC:

2523

ExAC

AF:

0.245

AC:

29730

Asia WGS

AF:

0.189

AC:

657

AN:

3478

EpiCase

AF:

0.279

EpiControl

AF:

0.286

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 10, 2018	- -

Pituitary hormone deficiency, combined, 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.088

DANN

Benign

0.58

DEOGEN2

Benign

0.070

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.24

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.25

REVEL

Benign

0.20

Sift

Benign

0.86

Sift4G

Benign

0.63

Polyphen

0.0

Vest4

0.0080

MPC

0.092

ClinPred

0.0024

GERP RS

-7.5

Varity_R

0.025

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over