rs2233783

chr5-177994296-C-Achr5-177994296-C-Gchr5-177994296-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_006261.5(PROP1):c.152G>T(p.Gly51Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G51A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: PROP1 NM_006261.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: -0.859

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 -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009972423).
• BP6: Variant 5-177994296-C-A is Benign according to our data. Variant chr5-177994296-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 742937.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000092 (14/152232) while in subpopulation EAS AF= 0.00174 (9/5166). AF 95% confidence interval is 0.000909. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROP1	NM_006261.5	c.152G>T	p.Gly51Val	missense_variant	2/3	ENST00000308304.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROP1	ENST00000308304.2	c.152G>T	p.Gly51Val	missense_variant	2/3	1	NM_006261.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152114 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000222 AC: 54 AN: 243052 Hom.: 0 AF XY: 0.000227 AC XY: 30 AN XY: 132006

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00215

Gnomad SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000739

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.0000589 AC: 86 AN: 1459246 Hom.: 0 Cov.: 32 AF XY: 0.0000565 AC XY: 41 AN XY: 725598

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00121

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152232 Hom.: 0 Cov.: 31 AF XY: 0.0000806 AC XY: 6 AN XY: 74434

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00000877 Hom.: 13

ExAC AF: 0.000223 AC: 27

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pituitary hormone deficiency, combined, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 24, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	0.011
Dann	Benign	0.16
DEOGEN2	Benign	0.088	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.00089	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	-1.2	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.17
Sift	Benign	0.58	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.32		Loss of methylation at R53 (P = 0.0557);
MVP		0.63
MPC		0.12
ClinPred		0.0065	T
GERP RS		-4.4
Varity_R		0.026
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2233783; hg19: chr5-177421297;