rs745483989

Variant names:

• chr19-47695362-CAGG-C
• rs745483989
• NM_001394372.1:c.3077-2_3077delAGG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PVS1 BP6_Moderate

The NM_001394372.1(BICRA):​c.3077-2_3077delAGG​(p.Gly1026fs) variant causes a frameshift, splice acceptor, splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. G1026G) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.028 (0 hom., cov: 0)
  • Exomes 𝑓: 0.013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BICRA NM_001394372.1 frameshift, splice_acceptor, splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

Genes affected

BICRA (HGNC:4332): (BRD4 interacting chromatin remodeling complex associated protein) Enables transcription regulator activator activity. Involved in positive regulation of transcription, DNA-templated. Located in nucleus. Part of SWI/SNF complex. Implicated in Coffin-Siris syndrome. [provided by Alliance of Genome Resources, Apr 2022]

BICRA Gene-Disease associations (from GenCC):

• Coffin-Siris syndrome 12

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

ENSG00000268746 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 19-47695362-CAGG-C is Benign according to our data. Variant chr19-47695362-CAGG-C is described in ClinVar as Benign. ClinVar VariationId is 402903.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BICRA	NM_001394372.1	c.3077-2_3077delAGG	p.Gly1026fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 15	ENST00000594866.3	NP_001381301.1
BICRA	NM_015711.3	c.3077-2_3077delAGG	p.Gly1026fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 15		NP_056526.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BICRA	ENST00000594866.3	c.3077-2_3077delAGG	p.Gly1026fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 15	2	NM_001394372.1	ENSP00000469738.2
BICRA	ENST00000396720.7	c.3077-2_3077delAGG	p.Gly1026fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 10 of 15	5		ENSP00000379946.2
BICRA	ENST00000614245.2	c.2351-2_2351delAGG	p.Gly784fs	frameshift_variant, splice_acceptor_variant, splice_region_variant, intron_variant	Exon 5 of 10	5		ENSP00000480219.2
ENSG00000268746	ENST00000599924.1	n.87-36702_87-36700delAGG		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 3525 AN: 123814 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0298

Gnomad AMI AF: 0.0292

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0204

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.00388

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0309

GnomAD2 exomes AF: 0.0962 AC: 11193 AN: 116306 AF XY: 0.0955

Gnomad AFR exome AF: 0.0894

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.102

Gnomad FIN exome AF: 0.0579

Gnomad NFE exome AF: 0.0927

Gnomad OTH exome AF: 0.103

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0135 AC: 13436 AN: 996828 Hom.: 0 AF XY: 0.0149 AC XY: 7529 AN XY: 503686

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0164 AC: 372 AN: 22726

American (AMR) AF: 0.0438 AC: 1303 AN: 29758

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 532 AN: 20874

East Asian (EAS) AF: 0.00945 AC: 292 AN: 30912

South Asian (SAS) AF: 0.0383 AC: 2495 AN: 65190

European-Finnish (FIN) AF: 0.0211 AC: 936 AN: 44318

Middle Eastern (MID) AF: 0.0155 AC: 50 AN: 3232

European-Non Finnish (NFE) AF: 0.00928 AC: 6833 AN: 736146

Other (OTH) AF: 0.0143 AC: 623 AN: 43672

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0285 AC: 3526 AN: 123926 Hom.: 0 Cov.: 0 AF XY: 0.0265 AC XY: 1623 AN XY: 61298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0297 AC: 1013 AN: 34074

American (AMR) AF: 0.0208 AC: 266 AN: 12772

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 94 AN: 2668

East Asian (EAS) AF: 0.0213 AC: 90 AN: 4232

South Asian (SAS) AF: 0.0207 AC: 85 AN: 4112

European-Finnish (FIN) AF: 0.0125 AC: 116 AN: 9286

Middle Eastern (MID) AF: 0.00417 AC: 1 AN: 240

European-Non Finnish (NFE) AF: 0.0330 AC: 1786 AN: 54052

Other (OTH) AF: 0.0305 AC: 54 AN: 1770

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.117 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=17/183	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.97		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745483989; hg19: chr19-48198619;