chr5-177992760-T-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The ENST00000308304.2(PROP1):​c.630A>T​(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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. P210P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROP1 ENST00000308304.2 synonymous
• Clinical Significance: Not reported in ClinVar
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP7: Synonymous conserved (PhyloP=0.321 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000308304.2. 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>T	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>T	p.Pro210Pro	synonymous	Exon 3 of 3	ENSP00000311290.2

Frequencies

GnomAD3 genomes AF: 0.000142 AC: 4 AN: 28224 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00109

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.000654

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000708

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 243200 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 126600

African (AFR) AF: 0.00 AC: 0 AN: 7480

American (AMR) AF: 0.00 AC: 0 AN: 14228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5108

East Asian (EAS) AF: 0.00 AC: 0 AN: 8440

South Asian (SAS) AF: 0.00 AC: 0 AN: 26172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 155988

Other (OTH) AF: 0.00 AC: 0 AN: 9282

GnomAD4 genome AF: 0.000142 AC: 4 AN: 28224 Hom.: 0 Cov.: 0 AF XY: 0.000299 AC XY: 4 AN XY: 13368

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

African (AFR) AF: 0.00 AC: 0 AN: 6958

American (AMR) AF: 0.00 AC: 0 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 752

East Asian (EAS) AF: 0.00109 AC: 1 AN: 920

South Asian (SAS) AF: 0.00113 AC: 1 AN: 886

European-Finnish (FIN) AF: 0.000654 AC: 1 AN: 1528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.0000708 AC: 1 AN: 14128

Other (OTH) AF: 0.00 AC: 0 AN: 374

⚠️ 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.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.9
DANN	Benign	0.51
PhyloP100		0.32

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;