rs4072924

Positions:

• chr5-177995822-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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. Variant chr5-177995822-C-T is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
PROP1	NM_006261.5	c.109+3G>A		splice_region_variant, intron_variant		ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.109+3G>A		splice_region_variant, intron_variant		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

GnomAD3 exomes AF: 0.507 AC: 127052 AN: 250828 Hom.: 32756 AF XY: 0.503 AC XY: 68262 AN XY: 135626

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 SAS 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

Gnomad4 AFR exome AF: 0.574

Gnomad4 AMR exome AF: 0.442

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.380

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.518

Gnomad4 NFE exome AF: 0.562

Gnomad4 OTH exome AF: 0.532

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

Gnomad4 AFR AF: 0.574

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.475

Gnomad4 EAS AF: 0.431

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.509

Gnomad4 NFE AF: 0.561

Gnomad4 OTH AF: 0.500

Alfa AF: 0.544 Hom.: 34317

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs4072924; hg19: chr5-177422823;