rs187384754

Variant names:

• chrX-80745587-G-A
• rs187384754
• NM_153252.5:c.573C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_153252.5(BRWD3):​c.573C>T​(p.Ser191Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000986 in 1,206,455 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 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 0.00015 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000093 (0 hom. 37 hem.)
• Consequence: BRWD3 NM_153252.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.448
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant X-80745587-G-A is Benign according to our data. Variant chrX-80745587-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 434542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.448 with no splicing effect.
• BS2: High AC in GnomAd4 at 17 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD3	NM_153252.5	MANE Select	c.573C>T	p.Ser191Ser	synonymous	Exon 7 of 41	NP_694984.5
	BRWD3	NM_001441339.1		c.573C>T	p.Ser191Ser	synonymous	Exon 7 of 40	NP_001428268.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRWD3	ENST00000373275.5	TSL:1 MANE Select	c.573C>T	p.Ser191Ser	synonymous	Exon 7 of 41	ENSP00000362372.4
	BRWD3	ENST00000478415.1	TSL:5	n.785C>T		non_coding_transcript_exon	Exon 7 of 8

Frequencies

GnomAD3 genomes AF: 0.000163 AC: 18 AN: 110522 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000973

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000173

Gnomad MID AF: 0.00844

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.000173 AC: 31 AN: 179689 AF XY: 0.000201

Gnomad AFR exome AF: 0.0000772

Gnomad AMR exome AF: 0.0000738

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000313

Gnomad OTH exome AF: 0.000226

GnomAD4 exome AF: 0.0000931 AC: 102 AN: 1095881 Hom.: 0 Cov.: 30 AF XY: 0.000102 AC XY: 37 AN XY: 361651

African (AFR) AF: 0.0000759 AC: 2 AN: 26340

American (AMR) AF: 0.0000856 AC: 3 AN: 35055

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19329

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30101

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53849

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40441

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4127

European-Non Finnish (NFE) AF: 0.000101 AC: 85 AN: 840648

Other (OTH) AF: 0.000152 AC: 7 AN: 45991

GnomAD4 genome AF: 0.000154 AC: 17 AN: 110574 Hom.: 0 Cov.: 23 AF XY: 0.000152 AC XY: 5 AN XY: 32908

African (AFR) AF: 0.00 AC: 0 AN: 30416

American (AMR) AF: 0.0000972 AC: 1 AN: 10287

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2636

East Asian (EAS) AF: 0.00 AC: 0 AN: 3510

South Asian (SAS) AF: 0.00 AC: 0 AN: 2601

European-Finnish (FIN) AF: 0.000173 AC: 1 AN: 5796

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.000208 AC: 11 AN: 52918

Other (OTH) AF: 0.00198 AC: 3 AN: 1513

Alfa AF: 0.000260 Hom.: 3

Bravo AF: 0.000162

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BRWD3-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	5.2
DANN	Benign	0.67
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs187384754; hg19: chrX-80001086; COSMIC: COSV100955752;