5-35065475-G-A

Position:

• chr5-35065475-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000949.7(PRLR):​c.1483C>T​(p.Pro495Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRLR NM_000949.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.904

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18728468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRLR	NM_000949.7	c.1483C>T	p.Pro495Ser	missense_variant	10/10	ENST00000618457.5	NP_000940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRLR	ENST00000618457.5	c.1483C>T	p.Pro495Ser	missense_variant	10/10	1	NM_000949.7	ENSP00000482954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial hyperprolactinemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

3billion

Mar 22, 2022

The variant is not observed in the gnomAD v2.1.1 dataset. A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.89
DEOGEN2	Benign	0.30	.;T;.
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.80	T;T;.
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Uncertain	-0.061	T
MutationAssessor	Uncertain	2.5	.;M;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-2.3	.;.;N
REVEL	Uncertain	0.46
Sift	Benign	0.20	.;.;T
Sift4G	Benign	0.19	T;T;T
Polyphen		1.0	D;B;D
Vest4		0.044
MutPred		0.55		.;Loss of catalytic residue at P495 (P = 0.0064);.;
MVP		0.84
ClinPred		0.36	T
GERP RS		3.0
Varity_R		0.056
gMVP		0.12

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: rs772553198; hg19: chr5-35065577; COSMIC: COSV105078432; COSMIC: COSV105078432;