X-80692090-T-G

Variant names:

• chrX-80692090-T-G
• rs372374523
• NM_153252.5:c.3324A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_153252.5(BRWD3):​c.3324A>C​(p.Gly1108Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 1,202,853 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1108G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 3 hem.)
• Consequence: BRWD3 NM_153252.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.45
• Publications: 0 publications found

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]

BRWD3 Gene-Disease associations (from GenCC):

• intellectual disability, X-linked 93

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• infantile spasms

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• self-limited epilepsy with centrotemporal spikes

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BS2: High AC in GnomAdExome4 at 7 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD3	NM_153252.5	c.3324A>C	p.Gly1108Gly	splice_region_variant, synonymous_variant	Exon 29 of 41	ENST00000373275.5	NP_694984.5
BRWD3	NM_001441339.1	c.3174A>C	p.Gly1058Gly	splice_region_variant, synonymous_variant	Exon 28 of 40		NP_001428268.1
BRWD3	XM_017029384.2	c.2112A>C	p.Gly704Gly	splice_region_variant, synonymous_variant	Exon 18 of 30		XP_016884873.1
BRWD3	XM_047441957.1	c.3324A>C	p.Gly1108Gly	splice_region_variant, synonymous_variant	Exon 29 of 38		XP_047297913.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5	c.3324A>C	p.Gly1108Gly	splice_region_variant, synonymous_variant	Exon 29 of 41	1	NM_153252.5	ENSP00000362372.4
BRWD3	ENST00000473691.1	n.1460A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 13 of 25	2

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111929 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182392 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000642 AC: 7 AN: 1090924 Hom.: 0 Cov.: 30 AF XY: 0.00000839 AC XY: 3 AN XY: 357544

African (AFR) AF: 0.00 AC: 0 AN: 26245

American (AMR) AF: 0.00 AC: 0 AN: 35179

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19328

East Asian (EAS) AF: 0.00 AC: 0 AN: 30152

South Asian (SAS) AF: 0.00 AC: 0 AN: 53664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3583

European-Non Finnish (NFE) AF: 0.00000837 AC: 7 AN: 836486

Other (OTH) AF: 0.00 AC: 0 AN: 45803

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111929 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34083

African (AFR) AF: 0.00 AC: 0 AN: 30848

American (AMR) AF: 0.00 AC: 0 AN: 10491

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3609

South Asian (SAS) AF: 0.00 AC: 0 AN: 2683

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53166

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.84
PhyloP100		2.4

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs372374523; hg19: chrX-79947589;