12-12465760-G-T

Variant names:

• chr12-12465760-G-T
• rs376478744
• NM_058169.6:c.575G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_058169.6(BORCS5):​c.575G>T​(p.Arg192Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BORCS5 NM_058169.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.38
• Publications: 0 publications found

Genes affected

BORCS5 (HGNC:17950): (BLOC-1 related complex subunit 5) Involved in lysosome localization and organelle transport along microtubule. Located in cytoplasmic side of lysosomal membrane and plasma membrane. Is intrinsic component of membrane. Part of BORC complex. Colocalizes with plus-end kinesin complex. [provided by Alliance of Genome Resources, Apr 2022]

BORCS5 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38473153).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058169.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BORCS5	NM_058169.6	MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 4 of 4	NP_477517.1	Q969J3-1
	BORCS5	NM_001300742.3		c.518G>T	p.Arg173Leu	missense	Exon 4 of 4	NP_001287671.1	G3V1P3
	BORCS5	NM_001330356.2		c.431G>T	p.Arg144Leu	missense	Exon 3 of 3	NP_001317285.1	Q969J3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BORCS5	ENST00000314565.9	TSL:1 MANE Select	c.575G>T	p.Arg192Leu	missense	Exon 4 of 4	ENSP00000321546.4	Q969J3-1
	BORCS5	ENST00000298571.6	TSL:1	c.431G>T	p.Arg144Leu	missense	Exon 3 of 3	ENSP00000298571.6	Q969J3-2
	BORCS5	ENST00000866053.1		c.638G>T	p.Arg213Leu	missense	Exon 5 of 5	ENSP00000536112.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460270 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726474

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111606

Other (OTH) AF: 0.00 AC: 0 AN: 60308

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
Eigen	Benign	0.034
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.89	T
PhyloP100		6.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.010	D
Polyphen		0.67	P
Vest4		0.62
MutPred		0.30		Loss of helix (P = 0.0558)
MVP		0.62
MPC		0.82
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.17
gMVP		0.65
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs376478744; hg19: chr12-12618694;