rs142085721

Variant names:

• chrX-80744248-T-G
• rs142085721
• NM_153252.5:c.597A>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000373275.5(BRWD3):​c.597A>C​(p.Ser199Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00819 in 1,197,146 control chromosomes in the GnomAD database, including 37 homozygotes. There are 3,004 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., 159 hem., cov: 23)
  • Exomes 𝑓: 0.0085 (33 hom. 2845 hem.)
• Consequence: BRWD3 ENST00000373275.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.131
• 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: 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-80744248-T-G is Benign according to our data. Variant chrX-80744248-T-G is described in ClinVar as Benign. ClinVar VariationId is 210543.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.131 with no splicing effect.
• BS2: High AC in GnomAd4 at 564 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000373275.5. 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.597A>C	p.Ser199Ser	synonymous	Exon 8 of 41	NP_694984.5
	BRWD3	NM_001441339.1		c.597A>C	p.Ser199Ser	synonymous	Exon 8 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.597A>C	p.Ser199Ser	synonymous	Exon 8 of 41	ENSP00000362372.4
	BRWD3	ENST00000478415.1	TSL:5	n.809A>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes AF: 0.00504 AC: 564 AN: 111934 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.00117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000287

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00476

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00927

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00490 AC: 897 AN: 183227 AF XY: 0.00460

Gnomad AFR exome AF: 0.000990

Gnomad AMR exome AF: 0.000475

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00955

Gnomad OTH exome AF: 0.00510

GnomAD4 exome AF: 0.00851 AC: 9239 AN: 1085163 Hom.: 33 Cov.: 28 AF XY: 0.00810 AC XY: 2845 AN XY: 351119

African (AFR) AF: 0.000917 AC: 24 AN: 26173

American (AMR) AF: 0.000370 AC: 13 AN: 35181

Ashkenazi Jewish (ASJ) AF: 0.000518 AC: 10 AN: 19317

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 53835

European-Finnish (FIN) AF: 0.00415 AC: 168 AN: 40520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4098

European-Non Finnish (NFE) AF: 0.0106 AC: 8789 AN: 830226

Other (OTH) AF: 0.00515 AC: 235 AN: 45661

GnomAD4 genome AF: 0.00504 AC: 564 AN: 111983 Hom.: 4 Cov.: 23 AF XY: 0.00465 AC XY: 159 AN XY: 34159

African (AFR) AF: 0.00117 AC: 36 AN: 30876

American (AMR) AF: 0.000287 AC: 3 AN: 10470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2710

European-Finnish (FIN) AF: 0.00476 AC: 29 AN: 6095

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00927 AC: 493 AN: 53180

Other (OTH) AF: 0.00197 AC: 3 AN: 1522

Alfa AF: 0.00589 Hom.: 81

Bravo AF: 0.00443

EpiCase AF: 0.00911

EpiControl AF: 0.00789

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, X-linked 93 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.8
DANN	Benign	0.67
PhyloP100		0.13
Mutation Taster		=67/33	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: rs142085721; hg19: chrX-79999747; COSMIC: COSV100956553;