6-22287467-A-C

Variant summary

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

The NM_000948.6(PRL):c.619T>G(p.Ser207Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PRL NM_000948.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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 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=0.3783675).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PRL	NM_000948.6	c.619T>G	p.Ser207Ala	missense_variant	5/5	ENST00000306482.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PRL	ENST00000306482.2	c.619T>G	p.Ser207Ala	missense_variant	5/5	1	NM_000948.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461820 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Jan 22, 2024

The c.619T>G (p.S207A) alteration is located in exon 5 (coding exon 5) of the PRL gene. This alteration results from a T to G substitution at nucleotide position 619, causing the serine (S) at amino acid position 207 to be replaced by an alanine (A). 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	Benign	0.29
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
Sift4G	Benign	0.11	T;D;T
Polyphen		0.88	P;.;B
Vest4		0.22
MutPred		0.69		.;.;Loss of phosphorylation at S207 (P = 0.0334);
MVP		0.92
MPC		1.2
ClinPred		0.97	D
GERP RS		1.7
Varity_R		0.52
gMVP		0.49

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: chr6-22287696;