X-103063171-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_018476.4(BEX1):c.104C>T(p.Ala35Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,209,789 control chromosomes in the GnomAD database, including 1 homozygotes. There are 179 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 3 hem., cov: 22)
  • Exomes 𝑓: 0.00044 (1 hom. 176 hem.)
• Consequence: BEX1 NM_018476.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.493

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0876317).
• BP6: Variant X-103063171-G-A is Benign according to our data. Variant chrX-103063171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2454286.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BEX1	NM_018476.4	c.104C>T	p.Ala35Val	missense_variant	3/3	ENST00000372728.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BEX1	ENST00000372728.4	c.104C>T	p.Ala35Val	missense_variant	3/3	1	NM_018476.4	P1

Frequencies

GnomAD3 genomes AF: 0.000215 AC: 24 AN: 111536 Hom.: 0 Cov.: 22 AF XY: 0.0000890 AC XY: 3 AN XY: 33726

Gnomad AFR AF: 0.0000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000377

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000218 AC: 40 AN: 183199 Hom.: 0 AF XY: 0.000251 AC XY: 17 AN XY: 67697

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000314

Gnomad FIN exome AF: 0.0000625

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000444 AC: 488 AN: 1098201 Hom.: 1 Cov.: 31 AF XY: 0.000484 AC XY: 176 AN XY: 363555

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000332

Gnomad4 FIN exome AF: 0.000148

Gnomad4 NFE exome AF: 0.000493

Gnomad4 OTH exome AF: 0.000781

GnomAD4 genome AF: 0.000215 AC: 24 AN: 111588 Hom.: 0 Cov.: 22 AF XY: 0.0000888 AC XY: 3 AN XY: 33788

Gnomad4 AFR AF: 0.0000651

Gnomad4 AMR AF: 0.0000949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000377

Gnomad4 OTH AF: 0.000660

Alfa AF: 0.000379 Hom.: 15

Bravo AF: 0.000174

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000709

EpiControl AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2023

The c.104C>T (p.A35V) 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 104, causing the alanine (A) at amino acid position 35 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

BEX1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Benign	0.0010	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.088	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.12
Sift	Benign	0.061	T
Sift4G	Uncertain	0.024	D
Polyphen		0.94	P
Vest4		0.044
MVP		0.29
MPC		0.088
ClinPred		0.063	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.24

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: rs140998909; hg19: chrX-102318099;