5-35065548-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000949.7(PRLR):c.1410G>A(p.Glu470=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,614,136 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (36 hom.)
• Consequence: PRLR NM_000949.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.16

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 5-35065548-C-T is Benign according to our data. Variant chr5-35065548-C-T is described in ClinVar as [Benign]. Clinvar id is 781625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.16 with no splicing effect.
• BS2: High AC in GnomAd at 575 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRLR	NM_000949.7	c.1410G>A	p.Glu470=	synonymous_variant	10/10	ENST00000618457.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRLR	ENST00000618457.5	c.1410G>A	p.Glu470=	synonymous_variant	10/10	1	NM_000949.7	P1

Frequencies

GnomAD3 genomes AF: 0.00378 AC: 575 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00600

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00379 AC: 954 AN: 251470 Hom.: 8 AF XY: 0.00399 AC XY: 542 AN XY: 135912

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00228

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00558 AC: 8158 AN: 1461888 Hom.: 36 Cov.: 31 AF XY: 0.00558 AC XY: 4061 AN XY: 727246

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00239

Gnomad4 ASJ exome AF: 0.00953

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000524

Gnomad4 NFE exome AF: 0.00657

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00378 AC: 575 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00339 AC XY: 252 AN XY: 74422

Gnomad4 AFR AF: 0.00111

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00600

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00573 Hom.: 1

Bravo AF: 0.00368

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00735

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

PRLR-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 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
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.33
Dann	Benign	0.30

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

Other links and lift over

dbSNP: rs62355478; hg19: chr5-35065650; COSMIC: COSV51495208; COSMIC: COSV51495208;