19-47675911-C-T

Position:

• chr19-47675911-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001394372.1(BICRA):​c.145C>T​(p.Pro49Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,270 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: 0.0000014 (0 hom.)
• Consequence: BICRA NM_001394372.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08506763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICRA	NM_001394372.1	c.145C>T	p.Pro49Ser	missense_variant	5/15	ENST00000594866.3	NP_001381301.1
BICRA	NM_015711.3	c.145C>T	p.Pro49Ser	missense_variant	5/15		NP_056526.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICRA	ENST00000594866.3	c.145C>T	p.Pro49Ser	missense_variant	5/15	2	NM_001394372.1	ENSP00000469738	P2
	ENST00000599924.1	n.87-56154C>T		intron_variant, non_coding_transcript_variant		5
BICRA	ENST00000396720.7	c.145C>T	p.Pro49Ser	missense_variant	5/15	5		ENSP00000379946	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452270 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721930

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: 0.0000236

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

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

Coffin-Siris syndrome 12 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Feb 09, 2023

A heterozygous missense variation in exon5 of the BICRA gene that results in the amino acid substitution of Serine for proline at codon 49 (p.Pro49Ser) was detected. The variant has not been reported in the 1000 genomes and gnomAD database. The in silico prediction of the variant is benign by PolyPhen-2 (HumDiv), SIFT, and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.0049	T;T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.58	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.085	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.81	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.12
Sift	Benign	0.30	T;.
Sift4G	Benign	0.87	T;T
Polyphen		0.60	P;.
Vest4		0.30
MutPred		0.26		Loss of relative solvent accessibility (P = 0.0186);Loss of relative solvent accessibility (P = 0.0186);
MVP		0.11
MPC		1.2
ClinPred		0.27	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.15

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: rs1385590427; hg19: chr19-48179168;