19-47675870-T-C

Position:

• chr19-47675870-T-C

Variant summary

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

The NM_001394372.1(BICRA):​c.104T>C​(p.Leu35Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BICRA NM_001394372.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BICRA	NM_001394372.1	c.104T>C	p.Leu35Pro	missense_variant	5/15	ENST00000594866.3	NP_001381301.1
BICRA	NM_015711.3	c.104T>C	p.Leu35Pro	missense_variant	5/15		NP_056526.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BICRA	ENST00000594866.3	c.104T>C	p.Leu35Pro	missense_variant	5/15	2	NM_001394372.1	ENSP00000469738	P2
	ENST00000599924.1	n.87-56195T>C		intron_variant, non_coding_transcript_variant		5
BICRA	ENST00000396720.7	c.104T>C	p.Leu35Pro	missense_variant	5/15	5		ENSP00000379946	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Apr 10, 2024

This sequence variant is a single nucleotide substitution (T>C) at position 104 of the coding sequence of the BICRA gene that results in a leucine to proline amino acid change at residue 35 of the BRD4 interacting chromatin remodeling complex associated protein. This variant is absent from ClinVar and has not been observed in individuals affected by a BICRA-related disorder in the published literature, to our knowledge. This variant is absent from the gnomAD v4.0.0 population database (0/~1,500,000 alleles). Bioinformatic tools are inconclusive if this amino acid change will be damaging or tolerated, and the Leu35 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.039	T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.28	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.31		Loss of stability (P = 0.0087);Loss of stability (P = 0.0087);
MVP		0.62
MPC		1.8
ClinPred		0.83	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-48179127;