5-177992760-T-G

Variant names:

• chr5-177992760-T-G
• rs535993919
• NM_006261.5:c.630A>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_006261.5(PROP1):​c.630A>C​(p.Pro210Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P210P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.321
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-177992760-T-G is Benign according to our data. Variant chr5-177992760-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287515.
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	NM_006261.5	MANE Select	c.630A>C	p.Pro210Pro	synonymous	Exon 3 of 3	NP_006252.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.630A>C	p.Pro210Pro	synonymous	Exon 3 of 3	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 1200 AN: 27374 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.0403

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.0379

Gnomad SAS AF: 0.0495

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0469

Gnomad OTH AF: 0.0698

GnomAD2 exomes AF: 0.00212 AC: 258 AN: 121552 AF XY: 0.00250

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.000467

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.000202

Gnomad FIN exome AF: 0.00241

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00156

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00145 AC: 351 AN: 242326 Hom.: 0 Cov.: 11 AF XY: 0.00155 AC XY: 195 AN XY: 126140

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000134 AC: 1 AN: 7462

American (AMR) AF: 0.00190 AC: 27 AN: 14174

Ashkenazi Jewish (ASJ) AF: 0.00256 AC: 13 AN: 5080

East Asian (EAS) AF: 0.000238 AC: 2 AN: 8420

South Asian (SAS) AF: 0.00146 AC: 38 AN: 26064

European-Finnish (FIN) AF: 0.00133 AC: 21 AN: 15788

Middle Eastern (MID) AF: 0.00294 AC: 2 AN: 680

European-Non Finnish (NFE) AF: 0.00149 AC: 232 AN: 155410

Other (OTH) AF: 0.00162 AC: 15 AN: 9248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0438 AC: 1200 AN: 27416 Hom.: 0 Cov.: 0 AF XY: 0.0433 AC XY: 564 AN XY: 13036

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0446 AC: 303 AN: 6794

American (AMR) AF: 0.0357 AC: 87 AN: 2436

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 31 AN: 732

East Asian (EAS) AF: 0.0379 AC: 34 AN: 896

South Asian (SAS) AF: 0.0495 AC: 43 AN: 868

European-Finnish (FIN) AF: 0.0207 AC: 31 AN: 1494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 50

European-Non Finnish (NFE) AF: 0.0469 AC: 641 AN: 13658

Other (OTH) AF: 0.0687 AC: 25 AN: 364

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.274 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	1	-	Pituitary hormone deficiency, combined, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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: rs535993919; hg19: chr5-177419761; COSMIC: COSV57644690;