chr5-177992355-C-T

Variant names:

• chr5-177992355-C-T
• rs4604209
• NM_006261.5:c.*354G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006261.5(PROP1):​c.*354G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 276,194 control chromosomes in the GnomAD database, including 8,819 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4870 hom., cov: 29)
  • Exomes 𝑓: 0.24 (3949 hom.)
• Consequence: PROP1 NM_006261.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0870
• Publications: 11 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=-0.94).
• BP6: Variant 5-177992355-C-T is Benign according to our data. Variant chr5-177992355-C-T is described in ClinVar as Benign. ClinVar VariationId is 353009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 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.*354G>A		3_prime_UTR	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.*354G>A		3_prime_UTR	Exon 3 of 3	ENSP00000311290.2	O75360

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37365 AN: 151652 Hom.: 4874 Cov.: 29

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.345

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.312

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.240

GnomAD4 exome AF: 0.237 AC: 29428 AN: 124424 Hom.: 3949 Cov.: 0 AF XY: 0.236 AC XY: 14834 AN XY: 62770

African (AFR) AF: 0.194 AC: 936 AN: 4828

American (AMR) AF: 0.142 AC: 872 AN: 6146

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 937 AN: 4422

East Asian (EAS) AF: 0.266 AC: 2750 AN: 10348

South Asian (SAS) AF: 0.163 AC: 826 AN: 5060

European-Finnish (FIN) AF: 0.278 AC: 1906 AN: 6868

Middle Eastern (MID) AF: 0.191 AC: 113 AN: 592

European-Non Finnish (NFE) AF: 0.246 AC: 19240 AN: 78116

Other (OTH) AF: 0.230 AC: 1848 AN: 8044

GnomAD4 genome AF: 0.246 AC: 37362 AN: 151770 Hom.: 4870 Cov.: 29 AF XY: 0.245 AC XY: 18143 AN XY: 74178

African (AFR) AF: 0.209 AC: 8649 AN: 41360

American (AMR) AF: 0.173 AC: 2633 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 824 AN: 3472

East Asian (EAS) AF: 0.345 AC: 1776 AN: 5150

South Asian (SAS) AF: 0.175 AC: 843 AN: 4808

European-Finnish (FIN) AF: 0.312 AC: 3271 AN: 10500

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18579 AN: 67922

Other (OTH) AF: 0.238 AC: 501 AN: 2104

Alfa AF: 0.250 Hom.: 6209

Bravo AF: 0.233

Asia WGS AF: 0.235 AC: 818 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pituitary hormone deficiency, combined, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	5.8
DANN	Benign	0.57
PhyloP100		-0.087
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: rs4604209; hg19: chr5-177419356; COSMIC: COSV57645295;