chrX-130005259-G-A

Variant names:

• chrX-130005259-G-A
• rs1325772447
• NM_001379451.1:c.28G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_001379451.1(BCORL1):​c.28G>A​(p.Gly10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,210,148 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: BCORL1 NM_001379451.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

Genes affected

BCORL1 (HGNC:25657): (BCL6 corepressor like 1) The protein encoded by this gene is a transcriptional corepressor that is found tethered to promoter regions by DNA-binding proteins. The encoded protein can interact with several different class II histone deacetylases to repress transcription. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16930732).
• BS2: High AC in GnomAdExome4 at 6 XL,AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCORL1	NM_001379451.1	c.28G>A	p.Gly10Ser	missense_variant	Exon 2 of 14	ENST00000540052.6	NP_001366380.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCORL1	ENST00000540052.6	c.28G>A	p.Gly10Ser	missense_variant	Exon 2 of 14	1	NM_001379451.1	ENSP00000437775.2
BCORL1	ENST00000218147.11	c.28G>A	p.Gly10Ser	missense_variant	Exon 2 of 13	5		ENSP00000218147.7
BCORL1	ENST00000607874.1	c.28G>A	p.Gly10Ser	missense_variant	Exon 3 of 3	3		ENSP00000484149.1
BCORL1	ENST00000488135.6	n.28G>A		non_coding_transcript_exon_variant	Exon 3 of 6	3		ENSP00000476643.1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112178 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183253 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000546 AC: 6 AN: 1097970 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363344

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.0000284 AC: 1 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54108

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000594 AC: 5 AN: 841963

Other (OTH) AF: 0.00 AC: 0 AN: 46076

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112178 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34344

African (AFR) AF: 0.00 AC: 0 AN: 30832

American (AMR) AF: 0.00 AC: 0 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3601

South Asian (SAS) AF: 0.00 AC: 0 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6121

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53257

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Uncertain	0.99
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;.;.
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.98	T
PhyloP100		2.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.88	.;N;N
REVEL	Benign	0.045
Sift	Uncertain	0.0030	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.36, 0.24
MutPred		0.27		Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);Gain of disorder (P = 0.0407);
MVP		0.45
MPC		0.41
ClinPred		0.66	D
GERP RS		3.9
gMVP		0.53
Mutation Taster		=82/18	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

Publications

LitVar

Other links and lift over

dbSNP: rs1325772447; hg19: chrX-129139235;