rs137853272

Positions:

• chrX-80677232-T-C
• chrX-80677232-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3 PP5

The ENST00000373275.5(BRWD3):​c.4786A>G​(p.Lys1596Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,097,003 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1596Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: BRWD3 ENST00000373275.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.61

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 5 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant X-80677232-T-C is Pathogenic according to our data. Variant chrX-80677232-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 10804.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRWD3	NM_153252.5	c.4786A>G	p.Lys1596Glu	missense_variant	41/41	ENST00000373275.5	NP_694984.5
BRWD3	XM_005262113.4	c.4636A>G	p.Lys1546Glu	missense_variant	40/40		XP_005262170.1
BRWD3	XM_017029384.2	c.3574A>G	p.Lys1192Glu	missense_variant	30/30		XP_016884873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5	c.4786A>G	p.Lys1596Glu	missense_variant	41/41	1	NM_153252.5	ENSP00000362372	P1
BRWD3	ENST00000473691.1			downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1097003 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362581

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, X-linked 93 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	0.032	A
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.012	D
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.64
MutPred		0.50		Loss of methylation at K1596 (P = 0.0186);
MVP		0.96
MPC		0.57
ClinPred		0.13	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.21

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: rs137853272; hg19: chrX-79932731;