12-124993818-C-G

Position:

• chr12-124993818-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_080626.6(BRI3BP):​c.28C>G​(p.Leu10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000308 in 974,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: BRI3BP NM_080626.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.780

Genes affected

BRI3BP (HGNC:14251): (BRI3 binding protein) Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048893303).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRI3BP	NM_080626.6	c.28C>G	p.Leu10Val	missense_variant	1/3	ENST00000341446.9
BRI3BP	XM_011537940.3	c.28C>G	p.Leu10Val	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRI3BP	ENST00000341446.9	c.28C>G	p.Leu10Val	missense_variant	1/3	1	NM_080626.6	P1
BRI3BP	ENST00000671775.2	c.28C>G	p.Leu10Val	missense_variant	1/3
BRI3BP	ENST00000672415.1	c.28C>G	p.Leu10Val	missense_variant	1/3			P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000308 AC: 3 AN: 974736 Hom.: 0 Cov.: 28 AF XY: 0.00000430 AC XY: 2 AN XY: 465280

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: 0.00000351

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Apr 28, 2023

The c.28C>G (p.L10V) alteration is located in exon 1 (coding exon 1) of the BRI3BP gene. This alteration results from a C to G substitution at nucleotide position 28, causing the leucine (L) at amino acid position 10 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	0.074
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.8
DANN	Benign	0.48
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.0060
Sift	Benign	0.23	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.23		Loss of disorder (P = 0.032);
MVP		0.13
MPC		0.67
ClinPred		0.083	T
GERP RS		-0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.063
gMVP		0.44

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: rs1406953822; hg19: chr12-125478364;