rs72478580

Positions:

chr5-35072610-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_000949.7(PRLR):c.508A>C(p.Ile170Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0238 in 1,614,040 control chromosomes in the GnomAD database, including 539 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 40 hom., cov: 32)

Exomes 𝑓: 0.024 ( 499 hom. )

Consequence

PRLR
NM_000949.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1B:2

Conservation

PhyloP100: 0.156

Variant links:

Genes affected

PRLR (HGNC:9446): (prolactin receptor) This gene encodes a receptor for the anterior pituitary hormone, prolactin, and belongs to the type I cytokine receptor family. Prolactin-dependent signaling occurs as the result of ligand-induced dimerization of the prolactin receptor. Several alternatively spliced transcript variants encoding different membrane-bound and soluble isoforms have been described for this gene, which may function to modulate the endocrine and autocrine effects of prolactin in normal tissue and cancer. [provided by RefSeq, Feb 2011]

PRLR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005667001).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0184 (2803/152282) while in subpopulation NFE AF= 0.0257 (1750/68006). AF 95% confidence interval is 0.0247. There are 40 homozygotes in gnomad4. There are 1326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 2803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRLR	NM_000949.7 link	c.508A>C	p.Ile170Leu	missense_variant	6/10	ENST00000618457.5	NP_000940.1	P16471-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRLR	ENST00000618457.5 link	c.508A>C	p.Ile170Leu	missense_variant	6/10	1	NM_000949.7	ENSP00000482954.1		P16471-1

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2800

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.0214

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0257

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.0188

AC:

4724

AN:

251230

Hom.:

AF XY:

0.0186

AC XY:

2520

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.00775

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0225

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00572

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.0272

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.0244

AC:

35608

AN:

1461758

Hom.:

499

Cov.:

AF XY:

0.0239

AC XY:

17397

AN XY:

727186

show subpopulations

Gnomad4 AFR exome

AF:

0.00848

Gnomad4 AMR exome

AF:

0.0153

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00539

Gnomad4 FIN exome

AF:

0.0240

Gnomad4 NFE exome

AF:

0.0278

Gnomad4 OTH exome

AF:

0.0222

GnomAD4 genome

AF:

0.0184

AC:

2803

AN:

152282

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1326

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00799

Gnomad4 AMR

AF:

0.0235

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00622

Gnomad4 FIN

AF:

0.0214

Gnomad4 NFE

AF:

0.0257

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0240

Hom.:

Bravo

AF:

0.0180

TwinsUK

AF:

0.0316

AC:

117

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0240

AC:

206

ExAC

AF:

0.0190

AC:

2305

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0268

EpiControl

AF:

0.0258

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Multiple fibroadenoma of the breast

Pathogenic:1Benign:1

Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000949.5:c.508A>C (Ile170Leu) was reported as I146L in the literature. Bogorad et al. used multiple functional assays, which unambiguously converge to the evidence that I146L exhibits constitutive activity, highlighting the remarkable effect of this single substitution on the biological properties of the PrlR (PMID: 24195502). This variant has an allele frequency of 0.027 in European (non-Finnish) subpopulation in the gnomAD database, including 71 homozygous occurrences. Taken together, we interprete this variant as Benign/Likely benign variant. ACMG/AMP criteria applied: BS1, BS2, PS3. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 21, 2013	- -

PRLR-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.5

DANN

Benign

0.58

DEOGEN2

Benign

0.17

.;.;.;.;.;.;.;T;.;.;.

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.70

.;.;T;T;T;.;T;T;.;.;T

MetaRNN

Benign

0.0057

T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.35

N;N;N;N;N;N;.;N;.;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.010

N;N;.;N;.;N;.;.;N;N;.

REVEL

Benign

0.044

Sift

Benign

1.0

T;T;.;T;.;T;.;.;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B;B;B;.;.

Vest4

0.16

ClinPred

0.0017

GERP RS

-1.0

Varity_R

0.12

gMVP

0.57

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over