rs996732250

chrX-14865459-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001018113.3(FANCB):c.52T>C(p.Tyr18His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,096,041 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. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y18F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000027 (0 hom. 1 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.63

Genes affected

FANCB (HGNC:3583): (FA complementation group B) This gene encodes a member of the Fanconi anemia complementation group B. This protein is assembled into a nucleoprotein complex that is involved in the repair of DNA lesions. Mutations in this gene can cause chromosome instability and VACTERL syndrome with hydrocephalus. [provided by RefSeq, Apr 2016]

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=0.30037963).
• BP6: Variant X-14865459-A-G is Benign according to our data. Variant chrX-14865459-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456186.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3	c.52T>C	p.Tyr18His	missense_variant	3/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1	c.52T>C	p.Tyr18His	missense_variant	3/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000550 AC: 1 AN: 181772 Hom.: 0 AF XY: 0.0000150 AC XY: 1 AN XY: 66886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 3 AN: 1096041 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 1 AN XY: 361925

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000238

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	May 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;D;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;M;.
MutationTaster	Benign	0.85	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.36
MutPred		0.52		Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);
MVP		0.31
MPC		0.21
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.62

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: rs996732250; hg19: chrX-14883581; COSMIC: COSV60759267;