chrX-80744022-C-G

Variant names:

• chrX-80744022-C-G
• rs55824836
• NM_153252.5:c.813+10G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153252.5(BRWD3):​c.813+10G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,194,197 control chromosomes in the GnomAD database, including 250 homozygotes. There are 8,561 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (21 hom., 548 hem., cov: 23)
  • Exomes 𝑓: 0.023 (229 hom. 8013 hem.)
• Consequence: BRWD3 NM_153252.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0210
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-80744022-C-G is Benign according to our data. Variant chrX-80744022-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 96518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0183 (2048/111610) while in subpopulation NFE AF = 0.0253 (1342/53080). AF 95% confidence interval is 0.0242. There are 21 homozygotes in GnomAd4. There are 548 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2048 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153252.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD3	NM_153252.5	MANE Select	c.813+10G>C		intron	N/A	NP_694984.5
	BRWD3	NM_001441339.1		c.813+10G>C		intron	N/A	NP_001428268.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD3	ENST00000373275.5	TSL:1 MANE Select	c.813+10G>C		intron	N/A	ENSP00000362372.4	Q6RI45-1
	BRWD3	ENST00000478415.1	TSL:5	n.1035G>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2048 AN: 111558 Hom.: 21 Cov.: 23

Gnomad AFR AF: 0.00345

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.0458

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00333

Gnomad FIN AF: 0.0265

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0253

Gnomad OTH AF: 0.0275

GnomAD2 exomes AF: 0.0194 AC: 3487 AN: 180103 AF XY: 0.0197

Gnomad AFR exome AF: 0.00275

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0451

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0255

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0230 AC: 24948 AN: 1082587 Hom.: 229 Cov.: 27 AF XY: 0.0229 AC XY: 8013 AN XY: 349619

African (AFR) AF: 0.00372 AC: 97 AN: 26060

American (AMR) AF: 0.0169 AC: 589 AN: 34855

Ashkenazi Jewish (ASJ) AF: 0.0498 AC: 955 AN: 19179

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30123

South Asian (SAS) AF: 0.00394 AC: 210 AN: 53239

European-Finnish (FIN) AF: 0.0286 AC: 1160 AN: 40507

Middle Eastern (MID) AF: 0.0211 AC: 86 AN: 4084

European-Non Finnish (NFE) AF: 0.0250 AC: 20731 AN: 828942

Other (OTH) AF: 0.0245 AC: 1118 AN: 45598

GnomAD4 genome AF: 0.0183 AC: 2048 AN: 111610 Hom.: 21 Cov.: 23 AF XY: 0.0162 AC XY: 548 AN XY: 33804

African (AFR) AF: 0.00345 AC: 106 AN: 30759

American (AMR) AF: 0.0230 AC: 241 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 121 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00334 AC: 9 AN: 2697

European-Finnish (FIN) AF: 0.0265 AC: 159 AN: 5996

Middle Eastern (MID) AF: 0.0279 AC: 6 AN: 215

European-Non Finnish (NFE) AF: 0.0253 AC: 1342 AN: 53080

Other (OTH) AF: 0.0271 AC: 41 AN: 1511

Alfa AF: 0.0244 Hom.: 194

Bravo AF: 0.0185

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	BRWD3-related disorder (1)
-	-	1	Intellectual disability, X-linked 93 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.4
DANN	Benign	0.75
PhyloP100		-0.021
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55824836; hg19: chrX-79999521;