5-35066018-A-G

Position:

• chr5-35066018-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000949.7(PRLR):​c.940T>C​(p.Tyr314His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 6.77

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36441866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRLR	NM_000949.7	c.940T>C	p.Tyr314His	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.940T>C	p.Tyr314His	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

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.940T>C (p.Y314H) alteration is located in exon 10 (coding exon 8) of the PRLR gene. This alteration results from a T to C substitution at nucleotide position 940, causing the tyrosine (Y) at amino acid position 314 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0071	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	.;.;.;D;.;.;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D;D;.;.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.5	L;L;.;L;.;L;L
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.8	D;.;.;.;D;D;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;.;.;.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.;.
Vest4		0.33
MutPred		0.48		Loss of phosphorylation at Y314 (P = 0.0084);Loss of phosphorylation at Y314 (P = 0.0084);.;Loss of phosphorylation at Y314 (P = 0.0084);.;Loss of phosphorylation at Y314 (P = 0.0084);Loss of phosphorylation at Y314 (P = 0.0084);
MVP		0.68
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.51
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-35066120; COSMIC: COSV51493346; COSMIC: COSV51493346;