Genetic Variant BROX:p.Ser78Cys (chr1-222719287-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144695.4(BROX):c.233C>G(p.Ser78Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000414 in 1,448,608 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

BROX
NM_144695.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.53

Variant links:

Genes affected

BROX (HGNC:26512): (BRO1 domain and CAAX motif containing) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

BROX links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BROX	NM_144695.4 link	c.233C>G	p.Ser78Cys	missense_variant	Exon 4 of 13	ENST00000340934.10	NP_653296.2	Q5VW32-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BROX	ENST00000340934.10 link	c.233C>G	p.Ser78Cys	missense_variant	Exon 4 of 13	1	NM_144695.4	ENSP00000343742.5		Q5VW32-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250764

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000414

AC:

AN:

1448608

Hom.:

Cov.:

AF XY:

0.00000554

AC XY:

AN XY:

721424

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000454

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.233C>G (p.S78C) alteration is located in exon 4 (coding exon 3) of the BROX gene. This alteration results from a C to G substitution at nucleotide position 233, causing the serine (S) at amino acid position 78 to be replaced by a cysteine (C). 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

0.086

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

T;.;.;.;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.92

D;D;.;D;D

M_CAP

Benign

0.0050

MetaRNN

Uncertain

0.44

T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.0

L;L;L;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.1

D;.;D;D;D

REVEL

Benign

0.093

Sift

Uncertain

0.013

D;.;D;D;D

Sift4G

Uncertain

0.044

D;D;D;D;D

Polyphen

0.89

P;.;.;P;.

Vest4

0.38

MutPred

0.60

Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);Loss of disorder (P = 0.0091);

MVP

0.67

MPC

0.090

ClinPred

0.58

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.37

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