5-177992760-T-G

Position:

• chr5-177992760-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006261.5(PROP1):​c.630A>C​(p.Pro210=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P210P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.321

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-177992760-T-G is Benign according to our data. Variant chr5-177992760-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287515.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROP1	NM_006261.5	c.630A>C	p.Pro210=	synonymous_variant	3/3	ENST00000308304.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROP1	ENST00000308304.2	c.630A>C	p.Pro210=	synonymous_variant	3/3	1	NM_006261.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1200 AN: 27374 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.0403

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0698

GnomAD3 exomes AF: 0.00212 AC: 258 AN: 121552 Hom.: 0 AF XY: 0.00250 AC XY: 163 AN XY: 65100

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.000202

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00241

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00156

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00145 AC: 351 AN: 242326 Hom.: 0 Cov.: 11 AF XY: 0.00155 AC XY: 195 AN XY: 126140

Gnomad4 AFR exome AF: 0.000134

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00256

Gnomad4 EAS exome AF: 0.000238

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00149

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0438 AC: 1200 AN: 27416 Hom.: 0 Cov.: 0 AF XY: 0.0433 AC XY: 564 AN XY: 13036

Gnomad4 AFR AF: 0.0446

Gnomad4 AMR AF: 0.0357

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.0379

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.0469

Gnomad4 OTH AF: 0.0687

Alfa AF: 0.274 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely 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: Silent, not in splice consensus -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 19, 2016	- -

Pituitary hormone deficiency, combined, 2 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.6
DANN	Benign	0.58

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: rs535993919; hg19: chr5-177419761; COSMIC: COSV57644690;