chr5-177992290-G-A

Variant names:

• chr5-177992290-G-A
• rs116225539
• NM_006261.5:c.*419C>T

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.*419C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 179,120 control chromosomes in the GnomAD database, including 173 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.028 (154 hom., cov: 29)
  • Exomes 𝑓: 0.018 (19 hom.)
• Consequence: PROP1 NM_006261.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0760

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 5-177992290-G-A is Benign according to our data. Variant chr5-177992290-G-A is described in ClinVar as [Benign]. Clinvar id is 353008.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROP1	NM_006261.5	c.*419C>T		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.*419C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 4297 AN: 151528 Hom.: 153 Cov.: 29

Gnomad AFR AF: 0.00868

Gnomad AMI AF: 0.00662

Gnomad AMR AF: 0.0239

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.0113

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0323

GnomAD4 exome AF: 0.0183 AC: 502 AN: 27480 Hom.: 19 Cov.: 0 AF XY: 0.0182 AC XY: 255 AN XY: 14016

Gnomad4 AFR exome AF: 0.00207

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0759

Gnomad4 SAS exome AF: 0.0954

Gnomad4 FIN exome AF: 0.00427

Gnomad4 NFE exome AF: 0.0135

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0284 AC: 4299 AN: 151640 Hom.: 154 Cov.: 29 AF XY: 0.0310 AC XY: 2299 AN XY: 74090

Gnomad4 AFR AF: 0.00863

Gnomad4 AMR AF: 0.0239

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.122

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.0113

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0319

Alfa AF: 0.0234 Hom.: 17

Bravo AF: 0.0247

Asia WGS AF: 0.128 AC: 445 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	1.9
DANN	Benign	0.23

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: rs116225539; hg19: chr5-177419291; COSMIC: COSV57645306;