rs1135320

Positions:

• chr5-177995907-A-G
• chr5-177995907-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006261.5(PROP1):​c.27T>C​(p.Ala9Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.452 in 1,613,148 control chromosomes in the GnomAD database, including 168,297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14007 hom., cov: 32)
  • Exomes 𝑓: 0.46 (154290 hom.)
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.04

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-177995907-A-G is Benign according to our data. Variant chr5-177995907-A-G is described in ClinVar as [Benign]. Clinvar id is 353017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-177995907-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.563 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROP1	NM_006261.5	c.27T>C	p.Ala9Ala	synonymous_variant	1/3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304.2	c.27T>C	p.Ala9Ala	synonymous_variant	1/3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63531 AN: 151834 Hom.: 13996 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.526

Gnomad EAS AF: 0.568

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.467

GnomAD3 exomes AF: 0.483 AC: 121262 AN: 251114 Hom.: 30162 AF XY: 0.489 AC XY: 66388 AN XY: 135772

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.556

Gnomad ASJ exome AF: 0.525

Gnomad EAS exome AF: 0.577

Gnomad SAS exome AF: 0.577

Gnomad FIN exome AF: 0.485

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.455 AC: 665221 AN: 1461196 Hom.: 154290 Cov.: 50 AF XY: 0.459 AC XY: 334033 AN XY: 726966

Gnomad4 AFR exome AF: 0.279

Gnomad4 AMR exome AF: 0.550

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.622

Gnomad4 SAS exome AF: 0.577

Gnomad4 FIN exome AF: 0.483

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.459

GnomAD4 genome AF: 0.418 AC: 63579 AN: 151952 Hom.: 14007 Cov.: 32 AF XY: 0.426 AC XY: 31626 AN XY: 74270

Gnomad4 AFR AF: 0.282

Gnomad4 AMR AF: 0.508

Gnomad4 ASJ AF: 0.526

Gnomad4 EAS AF: 0.568

Gnomad4 SAS AF: 0.581

Gnomad4 FIN AF: 0.490

Gnomad4 NFE AF: 0.439

Gnomad4 OTH AF: 0.470

Alfa AF: 0.427 Hom.: 7205

Bravo AF: 0.417

Asia WGS AF: 0.552 AC: 1916 AN: 3478

EpiCase AF: 0.463

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Fulgent Genetics, Fulgent Genetics	Oct 25, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 27, 2017	- -
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 -

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	-0.95
CADD	Benign	2.6
DANN	Benign	0.14

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

Other links and lift over

dbSNP: rs1135320; hg19: chr5-177422908; COSMIC: COSV57645313;