chr5-35072610-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

37 publications found

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 Gene-Disease associations (from GenCC):

familial hyperprolactinemia
Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

PRLR links:

ENSG00000301126 (HGNC:):

ENSG00000301126 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 2803 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRLR	NM_000949.7 link	c.508A>C	p.Ile170Leu	missense_variant	Exon 6 of 10	ENST00000618457.5	NP_000940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRLR	ENST00000618457.5 link	c.508A>C	p.Ile170Leu	missense_variant	Exon 6 of 10	1	NM_000949.7	ENSP00000482954.1

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

GnomAD2 exomes

AF:

0.0188

AC:

4724

AN:

251230

AF XY:

0.0186

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 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

African (AFR)

AF:

0.00848

AC:

284

AN:

33474

American (AMR)

AF:

0.0153

AC:

683

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0203

AC:

530

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00539

AC:

465

AN:

86232

European-Finnish (FIN)

AF:

0.0240

AC:

1281

AN:

53420

Middle Eastern (MID)

AF:

0.0258

AC:

149

AN:

5768

European-Non Finnish (NFE)

AF:

0.0278

AC:

30873

AN:

1111940

Other (OTH)

AF:

0.0222

AC:

1343

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1838

3676

5513

7351

9189

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1186

2372

3558

4744

5930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0184

AC:

2803

AN:

152282

Hom.:

Cov.:

AF XY:

0.0178

AC XY:

1326

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00799

AC:

332

AN:

41564

American (AMR)

AF:

0.0235

AC:

359

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0214

AC:

227

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0257

AC:

1750

AN:

68006

Other (OTH)

AF:

0.0194

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

142

284

427

569

711

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0235

Hom.:

141

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

Nov 21, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:curation

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. -

PRLR-related disorder

Benign:1

Jul 16, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

0.16

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

Mutation Taster

=98/2

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over