1-110454034-T-C

Position:

• chr1-110454034-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032414.3(PROK1):​c.146T>C​(p.Met49Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROK1 NM_032414.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

Genes affected

PROK1 (HGNC:18454): (prokineticin 1) The protein encoded by this gene induces proliferation, migration, and fenestration (the formation of membrane discontinuities) in capillary endothelial cells derived from endocrine glands. It has little or no effect on a variety of other endothelial and non-endothelial cell types. Its expression is restricted to the steroidogenic glands (ovary, testis, adrenal, and placenta), is induced by hypoxia, and often complementary to the expression of vascular endothelial growth factor (VEGF), suggesting that these molecules function in a coordinated manner. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROK1	NM_032414.3	c.146T>C	p.Met49Thr	missense_variant	2/3	ENST00000271331.4	NP_115790.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROK1	ENST00000271331.4	c.146T>C	p.Met49Thr	missense_variant	2/3	1	NM_032414.3	ENSP00000271331.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Aug 01, 2024

The c.146T>C (p.M49T) alteration is located in exon 2 (coding exon 2) of the PROK1 gene. This alteration results from a T to C substitution at nucleotide position 146, causing the methionine (M) at amino acid position 49 to be replaced by a threonine (T). 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	0.45
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.041	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.17	B
Vest4		0.53
MutPred		0.35		Gain of phosphorylation at M49 (P = 0.045);
MVP		0.91
MPC		0.33
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.59

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: chr1-110996656;