6-22290248-T-A

Position:

• chr6-22290248-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000948.6(PRL):​c.418A>T​(p.Ile140Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PRL NM_000948.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

PRL (HGNC:9445): (prolactin) This gene encodes the anterior pituitary hormone prolactin. This secreted hormone is a growth regulator for many tissues, including cells of the immune system. It may also play a role in cell survival by suppressing apoptosis, and it is essential for lactation. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2011]

CASC15 (HGNC:28245): (cancer susceptibility 15) This gene produces a long non-coding RNA that may regulate cell proliferation. This RNA is upregulated in hepatocellular carcinoma, where it is thought to function as an oncogene. However, some splice variants of this gene may function as a tumor suppressor in neuroblastoma and other tumor types. Circular RNA variants were observed at this gene. [provided by RefSeq, Dec 2017]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRL	NM_000948.6	c.418A>T	p.Ile140Phe	missense_variant	4/5	ENST00000306482.2	NP_000939.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRL	ENST00000306482.2	c.418A>T	p.Ile140Phe	missense_variant	4/5	1	NM_000948.6	ENSP00000302150.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Nov 21, 2024

The c.418A>T (p.I140F) alteration is located in exon 4 (coding exon 4) of the PRL gene. This alteration results from a A to T substitution at nucleotide position 418, causing the isoleucine (I) at amino acid position 140 to be replaced by a phenylalanine (F). 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	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	19
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.60	D;D;.
Eigen	Benign	0.034
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.6	.;.;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.9	.;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0060	.;.;D
Sift4G	Benign	0.095	T;T;T
Polyphen		0.99	D;.;B
Vest4		0.73
MutPred		0.80		.;.;Loss of methylation at K143 (P = 0.1384);
MVP		0.93
MPC		1.6
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.65
gMVP		0.55

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: chr6-22290477;