rs2228482

Variant names:

• chr5-35084545-T-C
• rs2228482
• NM_000949.7:c.298A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000949.7(PRLR):​c.298A>G​(p.Ile100Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,606,348 control chromosomes in the GnomAD database, including 1,841 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (456 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1385 hom.)
• Consequence: PRLR NM_000949.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0210
• Publications: 19 publications found

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

ENSG00000301126 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022225678).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRLR	NM_000949.7	c.298A>G	p.Ile100Val	missense_variant	Exon 5 of 10	ENST00000618457.5	NP_000940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRLR	ENST00000618457.5	c.298A>G	p.Ile100Val	missense_variant	Exon 5 of 10	1	NM_000949.7	ENSP00000482954.1

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9155 AN: 152174 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0509

Gnomad ASJ AF: 0.0484

Gnomad EAS AF: 0.0349

Gnomad SAS AF: 0.0890

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0293

Gnomad OTH AF: 0.0550

GnomAD2 exomes AF: 0.0406 AC: 9860 AN: 242978 AF XY: 0.0417

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.0411

Gnomad EAS exome AF: 0.0310

Gnomad FIN exome AF: 0.00501

Gnomad NFE exome AF: 0.0286

Gnomad OTH exome AF: 0.0362

GnomAD4 exome AF: 0.0352 AC: 51209 AN: 1454056 Hom.: 1385 Cov.: 31 AF XY: 0.0368 AC XY: 26617 AN XY: 723040

African (AFR) AF: 0.136 AC: 4484 AN: 33004

American (AMR) AF: 0.0288 AC: 1229 AN: 42620

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 1100 AN: 25944

East Asian (EAS) AF: 0.0333 AC: 1310 AN: 39372

South Asian (SAS) AF: 0.0858 AC: 7211 AN: 84040

European-Finnish (FIN) AF: 0.00549 AC: 293 AN: 53372

Middle Eastern (MID) AF: 0.0935 AC: 537 AN: 5746

European-Non Finnish (NFE) AF: 0.0292 AC: 32356 AN: 1109798

Other (OTH) AF: 0.0447 AC: 2689 AN: 60160

GnomAD4 genome AF: 0.0602 AC: 9171 AN: 152292 Hom.: 456 Cov.: 32 AF XY: 0.0595 AC XY: 4434 AN XY: 74464

African (AFR) AF: 0.130 AC: 5403 AN: 41548

American (AMR) AF: 0.0508 AC: 777 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0484 AC: 168 AN: 3468

East Asian (EAS) AF: 0.0350 AC: 181 AN: 5176

South Asian (SAS) AF: 0.0891 AC: 430 AN: 4826

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10628

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0293 AC: 1992 AN: 68034

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0410 Hom.: 662

Bravo AF: 0.0662

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.124 AC: 548

ESP6500EA AF: 0.0291 AC: 250

ExAC AF: 0.0434 AC: 5274

Asia WGS AF: 0.0530 AC: 183 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.0010
DANN	Benign	0.42
DEOGEN2	Benign	0.26	.;.;.;.;.;.;T;.;.;T;.;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.47	.;.;T;T;T;.;T;.;T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N;N;N;N;N;N;N;N;N;.;.;.
PhyloP100		0.021
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.14	N;N;.;N;.;N;.;N;.;N;N;N
REVEL	Benign	0.035
Sift	Benign	0.51	T;T;.;T;.;T;.;T;.;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T;T;T;T;T;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.0070
ClinPred		0.0020	T
GERP RS		3.4
Varity_R		0.072
gMVP		0.55
Mutation Taster		=97/3	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: rs2228482; hg19: chr5-35084647; COSMIC: COSV51498747; COSMIC: COSV51498747;