rs747819351

Variant names:

• chrX-14864859-C-G
• rs747819351
• NM_001018113.3:c.652G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001018113.3(FANCB):​c.652G>C​(p.Glu218Gln) 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 1,096,170 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E218A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.02
• 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=0.16536182).

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.652G>C	p.Glu218Gln	missense	Exon 3 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.652G>C	p.Glu218Gln	missense	Exon 3 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.652G>C	p.Glu218Gln	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.652G>C	p.Glu218Gln	missense	Exon 3 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.652G>C	p.Glu218Gln	missense	Exon 2 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.652G>C	p.Glu218Gln	missense	Exon 3 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182767 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096170 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 1 AN XY: 361622

African (AFR) AF: 0.00 AC: 0 AN: 26377

American (AMR) AF: 0.0000284 AC: 1 AN: 35203

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 54096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 840378

Other (OTH) AF: 0.00 AC: 0 AN: 46027

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)
-	1	-	Fanconi anemia complementation group B;C2931228:VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.0
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.084
Sift	Benign	0.088	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.060
MutPred		0.26		Gain of helix (P = 0.132)
MVP		0.30
MPC		0.44
ClinPred		0.63	D
GERP RS		3.7
Varity_R		0.15
Mutation Taster		=100/0	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: rs747819351; hg19: chrX-14882981;