5-177992657-C-T

Position:

• chr5-177992657-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_006261.5(PROP1):​c.*52G>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 0.0102 in 1,315,538 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0087 (14 hom., cov: 29)
  • Exomes 𝑓: 0.010 (90 hom.)
• Consequence: PROP1 NM_006261.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.11

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 5-177992657-C-T is Benign according to our data. Variant chr5-177992657-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 353011.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00865 (1292/149310) while in subpopulation NFE AF= 0.0121 (820/67738). AF 95% confidence interval is 0.0114. There are 14 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 29. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROP1	NM_006261.5	c.*52G>A		3_prime_UTR_variant	3/3	ENST00000308304.2	NP_006252.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROP1	ENST00000308304	c.*52G>A		3_prime_UTR_variant	3/3	1	NM_006261.5	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.00866 AC: 1292 AN: 149208 Hom.: 14 Cov.: 29

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.0651

Gnomad AMR AF: 0.00981

Gnomad ASJ AF: 0.0220

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00189

Gnomad FIN AF: 0.00765

Gnomad MID AF: 0.00649

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.0107

GnomAD4 exome AF: 0.0104 AC: 12148 AN: 1166228 Hom.: 90 Cov.: 16 AF XY: 0.0102 AC XY: 6000 AN XY: 585512

Gnomad4 AFR exome AF: 0.00141

Gnomad4 AMR exome AF: 0.00846

Gnomad4 ASJ exome AF: 0.0279

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.0107

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.00865 AC: 1292 AN: 149310 Hom.: 14 Cov.: 29 AF XY: 0.00864 AC XY: 627 AN XY: 72590

Gnomad4 AFR AF: 0.00212

Gnomad4 AMR AF: 0.00979

Gnomad4 ASJ AF: 0.0220

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.00765

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.0106

Alfa AF: 0.00969 Hom.: 4

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.87
DANN	Benign	0.41

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: rs2233787; hg19: chr5-177419658;