X-102153964-T-G

Variant names:

• chrX-102153964-T-G
• NM_001012978.3:c.302A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012978.3(BEX5):​c.302A>C​(p.His101Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,719 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: BEX5 NM_001012978.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

Genes affected

BEX5 (HGNC:27990): (brain expressed X-linked 5) Predicted to enable signaling receptor binding activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BEX5	NM_001012978.3	c.302A>C	p.His101Pro	missense_variant	Exon 3 of 3	ENST00000333643.4	NP_001012996.1
BEX5	NM_001159560.2	c.302A>C	p.His101Pro	missense_variant	Exon 3 of 3		NP_001153032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BEX5	ENST00000333643.4	c.302A>C	p.His101Pro	missense_variant	Exon 3 of 3	1	NM_001012978.3	ENSP00000328030.3
BEX5	ENST00000543160.5	c.302A>C	p.His101Pro	missense_variant	Exon 3 of 3	3		ENSP00000446054.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096719 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 362141

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.302A>C (p.H101P) alteration is located in exon 3 (coding exon 1) of the BEX5 gene. This alteration results from a A to C substitution at nucleotide position 302, causing the histidine (H) at amino acid position 101 to be replaced by a proline (P). 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	Uncertain	0.43
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.028	T;T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.86	D;.
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.57
MutPred		0.72		Gain of glycosylation at H101 (P = 0.0668);Gain of glycosylation at H101 (P = 0.0668);
MVP		0.55
MPC		0.96
ClinPred		0.82	D
GERP RS		4.0
Varity_R		0.56
gMVP		0.17

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-101408936;