5-177994274-C-T

Variant names:

• chr5-177994274-C-T
• rs2233784
• NM_006261.5:c.174G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006261.5(PROP1):​c.174G>A​(p.Pro58Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,613,438 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P58P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (146 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (118 hom.)
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -4.36
• Publications: 1 publications found

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]

PROP1 Gene-Disease associations (from GenCC):

• pituitary hormone deficiency, combined, 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• combined pituitary hormone deficiencies, genetic form

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• panhypopituitarism

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 5-177994274-C-T is Benign according to our data. Variant chr5-177994274-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36699.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0762 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006261.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	NM_006261.5	MANE Select	c.174G>A	p.Pro58Pro	synonymous	Exon 2 of 3	NP_006252.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.174G>A	p.Pro58Pro	synonymous	Exon 2 of 3	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.0224 AC: 3412 AN: 152062 Hom.: 146 Cov.: 31

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00585 AC: 1453 AN: 248574 AF XY: 0.00415

Gnomad AFR exome AF: 0.0841

Gnomad AMR exome AF: 0.00241

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000627

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00214 AC: 3130 AN: 1461256 Hom.: 118 Cov.: 32 AF XY: 0.00180 AC XY: 1311 AN XY: 726844

African (AFR) AF: 0.0800 AC: 2678 AN: 33476

American (AMR) AF: 0.00296 AC: 132 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53354

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000495 AC: 55 AN: 1111628

Other (OTH) AF: 0.00404 AC: 244 AN: 60352

GnomAD4 genome AF: 0.0225 AC: 3418 AN: 152182 Hom.: 146 Cov.: 31 AF XY: 0.0214 AC XY: 1590 AN XY: 74406

African (AFR) AF: 0.0784 AC: 3255 AN: 41518

American (AMR) AF: 0.00810 AC: 124 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67976

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.0199 Hom.: 58

Bravo AF: 0.0262

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Pituitary hormone deficiency, combined, 2 (2)
-	-	1	Combined pituitary hormone deficiencies, genetic form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.6
DANN	Benign	0.77
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2233784; hg19: chr5-177421275;