X-103063067-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018476.4(BEX1):c.208C>T(p.Leu70Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,266 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: BEX1 NM_018476.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.525

Genes affected

BEX1 (HGNC:1036): (brain expressed X-linked 1) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity. Involved in positive regulation of DNA-binding transcription factor activity and positive regulation of transcription by RNA polymerase II. Part of transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29697502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEX1	NM_018476.4	c.208C>T	p.Leu70Phe	missense_variant	3/3	ENST00000372728.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEX1	ENST00000372728.4	c.208C>T	p.Leu70Phe	missense_variant	3/3	1	NM_018476.4	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098266 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363620

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.208C>T (p.L70F) alteration is located in exon 3 (coding exon 1) of the BEX1 gene. This alteration results from a C to T substitution at nucleotide position 208, causing the leucine (L) at amino acid position 70 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.10
Sift	Benign	0.040	D
Sift4G	Benign	0.092	T
Polyphen		0.99	D
Vest4		0.19
MutPred		0.31		Loss of catalytic residue at L70 (P = 0.0269);
MVP		0.22
MPC		0.13
ClinPred		0.56	D
GERP RS		1.1
Varity_R		0.13
gMVP		0.11

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-102317995;