5-177994296-C-G

Position:

chr5-177994296-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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=0.0019489825).

BP6

Variant 5-177994296-C-G is Benign according to our data. Variant chr5-177994296-C-G is described in ClinVar as [Benign]. Clinvar id is 188820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177994296-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.097 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.152G>C	p.Gly51Ala	missense_variant	2/3	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.152G>C	p.Gly51Ala	missense_variant	2/3	1	NM_006261.5	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

GnomAD3 exomes

AF:

0.00764

AC:

1857

AN:

243052

Hom.:

AF XY:

0.00551

AC XY:

727

AN XY:

132006

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 SAS exome

AF:

0.000330

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

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.00505

Gnomad4 ASJ exome

AF:

0.000499

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000344

Gnomad4 OTH exome

AF:

0.00639

GnomAD4 genome

AF:

0.0286

AC:

4353

AN:

152216

Hom.:

189

Cov.:

AF XY:

0.0272

AC XY:

2021

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.0996

Gnomad4 AMR

AF:

0.00824

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000565

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.0156

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

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2018	This variant is associated with the following publications: (PMID: 27884173, 16544023, 25525159, 20981092) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 13, 2016	- -

Pituitary hormone deficiency, combined, 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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. -
Benign, criteria provided, single submitter	literature only	Counsyl	Jun 05, 2014	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.010

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

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

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

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