Genetic Variant BRI3:p.Pro5Ala (chr7-98281808-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_015379.5(BRI3):c.13C>G(p.Pro5Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000134 in 149,316 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: 𝑓 0.000013 ( 0 hom., cov: 32)

Consequence

BRI3
NM_015379.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.61

Variant links:

Genes affected

BRI3 (HGNC:1109): (brain protein I3) Enables identical protein binding activity. Predicted to be located in azurophil granule membrane and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

BRI3 links:

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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=0.25687045).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRI3	NM_015379.5 link	c.13C>G	p.Pro5Ala	missense_variant	Exon 1 of 3	ENST00000297290.4	NP_056194.1	O95415-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRI3	ENST00000297290.4 link	c.13C>G	p.Pro5Ala	missense_variant	Exon 1 of 3	1	NM_015379.5	ENSP00000297290.3		O95415-1

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149316

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149316

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

72800

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13C>G (p.P5A) alteration is located in exon 1 (coding exon 1) of the BRI3 gene. This alteration results from a C to G substitution at nucleotide position 13, causing the proline (P) at amino acid position 5 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

0.15

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.063

T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.69

T;T

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.0

.;L

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.3

D;N

REVEL

Benign

0.22

Sift

Benign

0.035

D;D

Sift4G

Uncertain

0.036

D;T

Polyphen

1.0

D;B

Vest4

0.45

MutPred

0.47

Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);

MVP

0.45

MPC

0.35

ClinPred

0.67

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.17

gMVP

0.48

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