rs1800197

Variant names:

• chr5-177992966-C-T
• rs1800197
• NM_006261.5:c.424G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

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. 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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.439
• Publications: 30 publications found

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

ACMG classification

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

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_006261.5
• 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 VariationId is 196434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.424G>A	p.Ala142Thr	missense_variant	Exon 3 of 3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.424G>A	p.Ala142Thr	missense_variant	Exon 3 of 3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34381 AN: 151696 Hom.: 4324 Cov.: 30

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

GnomAD2 exomes AF: 0.248 AC: 62009 AN: 250184 AF XY: 0.250

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 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.: 56 AF XY: 0.275 AC XY: 199803 AN XY: 726872

African (AFR) AF: 0.129 AC: 4325 AN: 33480

American (AMR) AF: 0.299 AC: 13325 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 6288 AN: 26130

East Asian (EAS) AF: 0.0825 AC: 3275 AN: 39688

South Asian (SAS) AF: 0.246 AC: 21228 AN: 86190

European-Finnish (FIN) AF: 0.215 AC: 11457 AN: 53384

Middle Eastern (MID) AF: 0.194 AC: 1112 AN: 5744

European-Non Finnish (NFE) AF: 0.294 AC: 326568 AN: 1111624

Other (OTH) AF: 0.262 AC: 15815 AN: 60366

GnomAD4 genome AF: 0.227 AC: 34391 AN: 151814 Hom.: 4323 Cov.: 30 AF XY: 0.224 AC XY: 16637 AN XY: 74152

African (AFR) AF: 0.133 AC: 5493 AN: 41436

American (AMR) AF: 0.281 AC: 4281 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 821 AN: 3462

East Asian (EAS) AF: 0.0838 AC: 433 AN: 5170

South Asian (SAS) AF: 0.241 AC: 1162 AN: 4814

European-Finnish (FIN) AF: 0.198 AC: 2080 AN: 10492

Middle Eastern (MID) AF: 0.226 AC: 66 AN: 292

European-Non Finnish (NFE) AF: 0.285 AC: 19369 AN: 67904

Other (OTH) AF: 0.223 AC: 470 AN: 2106

Alfa AF: 0.266 Hom.: 25136

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

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 10, 2018

Athena Diagnostics

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

- -

Pituitary hormone deficiency, combined, 2 Benign:3

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 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. -

not specified Benign:2

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 -

Dec 15, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.088
DANN	Benign	0.58
DEOGEN2	Benign	0.070	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0017	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.44
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.20
Sift	Benign	0.86	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.092
ClinPred		0.0024	T
GERP RS		-7.5
Varity_R		0.025
gMVP		0.62
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1800197; hg19: chr5-177419967; COSMIC: COSV57644712;