rs797045418

Positions:

• chrX-80691114-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_153252.5(BRWD3):​c.3541G>A​(p.Val1181Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: BRWD3 NM_153252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

BRWD3 (HGNC:17342): (bromodomain and WD repeat domain containing 3) The protein encoded by this gene contains a bromodomain and several WD repeats. It is thought to have a chromatin-modifying function, and may thus play a role in transcription. Mutations in this gene are associated with a spectrum of cognitive disabilities and X-linked macrocephaly. This gene is also associated with translocations in patients with B-cell chronic lymphocytic leukemia. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BRWD3. . Gene score misZ 4.269 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked syndromic intellectual disability, West syndrome, intellectual disability, X-linked 93, childhood epilepsy with centrotemporal spikes.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRWD3	NM_153252.5	c.3541G>A	p.Val1181Ile	missense_variant	31/41	ENST00000373275.5
BRWD3	XM_005262113.4	c.3391G>A	p.Val1131Ile	missense_variant	30/40
BRWD3	XM_017029384.2	c.2329G>A	p.Val777Ile	missense_variant	20/30
BRWD3	XM_047441957.1	c.3541G>A	p.Val1181Ile	missense_variant	31/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRWD3	ENST00000373275.5	c.3541G>A	p.Val1181Ile	missense_variant	31/41	1	NM_153252.5	P1
BRWD3	ENST00000473691.1	n.1677G>A		non_coding_transcript_exon_variant	15/25	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 21, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.79	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.15
Sift	Benign	0.11	T
Sift4G	Benign	0.067	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.49		Loss of catalytic residue at V1181 (P = 0.0055);
MVP		0.55
MPC		1.7
ClinPred		0.92	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.55

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: rs797045418; hg19: chrX-79946613;