rs145883811

Variant names:

• chr5-177992919-G-A
• rs145883811
• NM_006261.5:c.471C>T

Your query was ambiguous. Multiple possible variants found:

• chr5-177992919-G-A
• chr5-177992919-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_006261.5(PROP1):​c.471C>T​(p.Tyr157Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,826 control chromosomes in the GnomAD database, including 6 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 0.0012 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (5 hom.)
• Consequence: PROP1 NM_006261.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 1.52
• Publications: 0 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health, Ambry Genetics
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 5-177992919-G-A is Benign according to our data. Variant chr5-177992919-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 286283.
• BP7: Synonymous conserved (PhyloP=1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00122 (185/152144) while in subpopulation AMR AF = 0.0017 (26/15264). AF 95% confidence interval is 0.00119. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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.471C>T	p.Tyr157Tyr	synonymous	Exon 3 of 3	NP_006252.4	O75360

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROP1	ENST00000308304.2	TSL:1 MANE Select	c.471C>T	p.Tyr157Tyr	synonymous	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152026 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.00106 AC: 265 AN: 250748 AF XY: 0.000952

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00388

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00133 AC: 1938 AN: 1461682 Hom.: 5 Cov.: 41 AF XY: 0.00129 AC XY: 936 AN XY: 727104

African (AFR) AF: 0.00161 AC: 54 AN: 33476

American (AMR) AF: 0.00110 AC: 49 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 98 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.000476 AC: 41 AN: 86212

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00145 AC: 1616 AN: 1111948

Other (OTH) AF: 0.00129 AC: 78 AN: 60384

GnomAD4 genome AF: 0.00122 AC: 185 AN: 152144 Hom.: 1 Cov.: 30 AF XY: 0.00130 AC XY: 97 AN XY: 74386

African (AFR) AF: 0.00123 AC: 51 AN: 41510

American (AMR) AF: 0.00170 AC: 26 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00137 AC: 93 AN: 67992

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

Alfa AF: 0.00161 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00164

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	1	Pituitary hormone deficiency, combined, 2 (2)
-	1	-	not specified (1)
-	-	1	PROP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.9
DANN	Benign	0.24
PhyloP100		1.5
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: rs145883811; hg19: chr5-177419920; COSMIC: COSV57644760;