Variant 5-139392749-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001161546.2(PROB1):c.2333C>T(p.Pro778Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000795 in 1,433,364 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 1 hom. )

Consequence

PROB1
NM_001161546.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

Variant links:

Genes affected

PROB1 (HGNC:41906): (proline rich basic protein 1) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PROB1 links:

SPATA24 (HGNC:):

SPATA24 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.13799241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PROB1	NM_001161546.2 linkuse as main transcript	c.2333C>T	p.Pro778Leu	missense_variant	1/1	ENST00000434752.4	NP_001155018.1
SPATA24	XM_005271916.5 linkuse as main transcript	c.*3456C>T		3_prime_UTR_variant	6/6		XP_005271973.1
SPATA24	XM_011543252.3 linkuse as main transcript	c.*3456C>T		3_prime_UTR_variant	6/6		XP_011541554.1
SPATA24	XM_011543253.3 linkuse as main transcript	c.*3456C>T		3_prime_UTR_variant	6/6		XP_011541555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROB1	ENST00000434752.4 linkuse as main transcript	c.2333C>T	p.Pro778Leu	missense_variant	1/1		NM_001161546.2	ENSP00000416033	P1

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00641

Gnomad NFE

AF:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000656

AC:

AN:

61008

Hom.:

AF XY:

0.0000981

AC XY:

AN XY:

30572

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000108

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000562

GnomAD4 exome

AF:

0.0000804

AC:

103

AN:

1281394

Hom.:

Cov.:

AF XY:

0.0000822

AC XY:

AN XY:

620714

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000547

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000516

Gnomad4 FIN exome

AF:

0.0000234

Gnomad4 NFE exome

AF:

0.0000576

Gnomad4 OTH exome

AF:

0.0000947

GnomAD4 genome

AF:

0.0000724

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000880

Hom.:

Bravo

AF:

0.0000453

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2023

The c.2333C>T (p.P778L) alteration is located in exon 1 (coding exon 1) of the PROB1 gene. This alteration results from a C to T substitution at nucleotide position 2333, causing the proline (P) at amino acid position 778 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.076

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.59

MutationAssessor

Benign

1.8

MutationTaster

Benign

0.99

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.17

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.24

MutPred

0.30

Gain of sheet (P = 0.0166);

MVP

0.27

ClinPred

0.36

GERP RS

4.0

Varity_R

0.23

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over