rs996732250

Variant names:

• chrX-14865459-A-G
• rs996732250
• NM_001018113.3:c.52T>C

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/20 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:2 B:1
• Conservation: PhyloP100: 3.63
• Publications: 0 publications found

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]

FANCB Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group B

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• VACTERL association, X-linked, with or without hydrocephalus

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• VACTERL with hydrocephalus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 456186.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018113.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	NM_001018113.3	MANE Select	c.52T>C	p.Tyr18His	missense	Exon 3 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.52T>C	p.Tyr18His	missense	Exon 3 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.52T>C	p.Tyr18His	missense	Exon 3 of 10	NP_001311091.1	Q8NB91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.52T>C	p.Tyr18His	missense	Exon 3 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.52T>C	p.Tyr18His	missense	Exon 2 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.52T>C	p.Tyr18His	missense	Exon 3 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000550 AC: 1 AN: 181772 AF XY: 0.0000150

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26368

American (AMR) AF: 0.00 AC: 0 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30141

South Asian (SAS) AF: 0.00 AC: 0 AN: 54089

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841185

Other (OTH) AF: 0.00 AC: 0 AN: 46046

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Fanconi anemia (2)
-	1	-	Fanconi anemia complementation group B (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.6
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.36
MutPred		0.52		Gain of disorder (P = 0.0205)
MVP		0.31
MPC		0.21
ClinPred		0.97	D
GERP RS		3.3
Varity_R		0.62
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

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