X-80677232-T-G

Variant names:

• chrX-80677232-T-G
• rs137853272
• NM_153252.5:c.4786A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153252.5(BRWD3):​c.4786A>C​(p.Lys1596Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: BRWD3 NM_153252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17278528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD3	NM_153252.5	c.4786A>C	p.Lys1596Gln	missense_variant	Exon 41 of 41	ENST00000373275.5	NP_694984.5
BRWD3	XM_005262113.4	c.4636A>C	p.Lys1546Gln	missense_variant	Exon 40 of 40		XP_005262170.1
BRWD3	XM_017029384.2	c.3574A>C	p.Lys1192Gln	missense_variant	Exon 30 of 30		XP_016884873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD3	ENST00000373275.5	c.4786A>C	p.Lys1596Gln	missense_variant	Exon 41 of 41	1	NM_153252.5	ENSP00000362372.4
BRWD3	ENST00000473691.1	n.*13A>C		downstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000182 AC: 2 AN: 1097003 Hom.: 0 Cov.: 31 AF XY: 0.00000552 AC XY: 2 AN XY: 362581

Gnomad4 AFR exome AF: 0.0000379

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.063
Sift	Uncertain	0.014	D
Sift4G	Benign	0.13	T
Polyphen		0.012	B
Vest4		0.23
MutPred		0.31		Loss of methylation at K1596 (P = 0.0186);
MVP		0.75
MPC		0.47
ClinPred		0.12	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.19

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;