rs4072924

Variant names:

• chr5-177995822-C-T
• rs4072924
• NM_006261.5:c.109+3G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006261.5(PROP1):​c.109+3G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 1,611,710 control chromosomes in the GnomAD database, including 238,286 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22452 hom., cov: 34)
  • Exomes 𝑓: 0.54 (215834 hom.)
• Consequence: PROP1 NM_006261.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001374
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.208
• Publications: 20 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 5-177995822-C-T is Benign according to our data. Variant chr5-177995822-C-T is described in ClinVar as [Benign]. Clinvar id is 353016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.109+3G>A		splice_region_variant, intron_variant	Intron 1 of 2	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.109+3G>A		splice_region_variant, intron_variant	Intron 1 of 2	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.541 AC: 82161 AN: 151998 Hom.: 22441 Cov.: 34

Gnomad AFR AF: 0.574

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.478

Gnomad ASJ AF: 0.475

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.422

Gnomad FIN AF: 0.509

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.503

GnomAD2 exomes AF: 0.507 AC: 127052 AN: 250828 AF XY: 0.503

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.476

Gnomad EAS exome AF: 0.424

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.554

Gnomad OTH exome AF: 0.515

GnomAD4 exome AF: 0.541 AC: 789333 AN: 1459594 Hom.: 215834 Cov.: 36 AF XY: 0.537 AC XY: 390082 AN XY: 726232

African (AFR) AF: 0.574 AC: 19201 AN: 33440

American (AMR) AF: 0.442 AC: 19755 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 12416 AN: 26120

East Asian (EAS) AF: 0.380 AC: 15071 AN: 39696

South Asian (SAS) AF: 0.424 AC: 36512 AN: 86198

European-Finnish (FIN) AF: 0.518 AC: 27288 AN: 52720

Middle Eastern (MID) AF: 0.406 AC: 2317 AN: 5706

European-Non Finnish (NFE) AF: 0.562 AC: 624677 AN: 1110668

Other (OTH) AF: 0.532 AC: 32096 AN: 60332

GnomAD4 genome AF: 0.540 AC: 82215 AN: 152116 Hom.: 22452 Cov.: 34 AF XY: 0.534 AC XY: 39731 AN XY: 74360

African (AFR) AF: 0.574 AC: 23810 AN: 41506

American (AMR) AF: 0.478 AC: 7306 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.475 AC: 1649 AN: 3468

East Asian (EAS) AF: 0.431 AC: 2225 AN: 5158

South Asian (SAS) AF: 0.420 AC: 2025 AN: 4824

European-Finnish (FIN) AF: 0.509 AC: 5382 AN: 10570

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.561 AC: 38119 AN: 67980

Other (OTH) AF: 0.500 AC: 1055 AN: 2112

Alfa AF: 0.544 Hom.: 42114

Bravo AF: 0.536

Asia WGS AF: 0.439 AC: 1527 AN: 3478

EpiCase AF: 0.537

EpiControl AF: 0.541

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Benign:3

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. -

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 -

Jul 27, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.21
PromoterAI		0.076	Neutral
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.0
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: rs4072924; hg19: chr5-177422823;