1-222727185-A-G

Variant names:

• chr1-222727185-A-G
• rs749849840
• NM_144695.4:c.598A>G

Variant summary

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

The NM_144695.4(BROX):​c.598A>G​(p.Ile200Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,460,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: BROX NM_144695.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.46

Genes affected

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

ACMG classification

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	c.598A>G	p.Ile200Val	missense_variant	Exon 8 of 13	ENST00000340934.10	NP_653296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BROX	ENST00000340934.10	c.598A>G	p.Ile200Val	missense_variant	Exon 8 of 13	1	NM_144695.4	ENSP00000343742.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250264 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135250

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460404 Hom.: 0 Cov.: 29 AF XY: 0.00000413 AC XY: 3 AN XY: 726552

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.598A>G (p.I200V) alteration is located in exon 8 (coding exon 7) of the BROX gene. This alteration results from a A to G substitution at nucleotide position 598, causing the isoleucine (I) at amino acid position 200 to be replaced by a valine (V). 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	0.063
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.051	T;.;.;.;.
Eigen	Benign	-0.043
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D;.;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.45	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.44	N;.;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.47	T;.;T;T;T
Sift4G	Benign	0.51	T;T;T;T;T
Polyphen		0.060	B;.;.;B;.
Vest4		0.56
MutPred		0.81		Loss of ubiquitination at K203 (P = 0.1264);.;.;Loss of ubiquitination at K203 (P = 0.1264);Loss of ubiquitination at K203 (P = 0.1264);
MVP		0.28
MPC		0.086
ClinPred		0.47	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.22

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

Other links and lift over

dbSNP: rs749849840; hg19: chr1-222900527;