rs4604209

Variant names:

• chr5-177992355-C-T
• rs4604209
• NM_006261.5:c.*354G>A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006261.5(PROP1):​c.*354G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 276,194 control chromosomes in the GnomAD database, including 8,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4870 hom., cov: 29)
  • Exomes 𝑓: 0.24 (3949 hom.)
• Consequence: PROP1 NM_006261.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0870

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-177992355-C-T is Benign according to our data. Variant chr5-177992355-C-T is described in ClinVar as [Benign]. Clinvar id is 353009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.*354G>A		3_prime_UTR_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	c.*354G>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37365 AN: 151652 Hom.: 4874 Cov.: 29

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.237 AC: 29428 AN: 124424 Hom.: 3949 Cov.: 0 AF XY: 0.236 AC XY: 14834 AN XY: 62770

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.142

Gnomad4 ASJ exome AF: 0.212

Gnomad4 EAS exome AF: 0.266

Gnomad4 SAS exome AF: 0.163

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.246

Gnomad4 OTH exome AF: 0.230

GnomAD4 genome AF: 0.246 AC: 37362 AN: 151770 Hom.: 4870 Cov.: 29 AF XY: 0.245 AC XY: 18143 AN XY: 74178

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.345

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.312

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.238

Alfa AF: 0.253 Hom.: 4822

Bravo AF: 0.233

Asia WGS AF: 0.235 AC: 818 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.8
DANN	Benign	0.57

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: rs4604209; hg19: chr5-177419356; COSMIC: COSV57645295;