rs764817410

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001018113.3(FANCB):c.1349G>A(p.Cys450Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,158,709 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. 12/19 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. C450F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000016 ( 0 hom. 8 hem. )

Consequence

FANCB
NM_001018113.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.29

Publications

0 publications found

Variant links:

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

FANCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant X-14850652-C-T is Benign according to our data. Variant chrX-14850652-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456176.

BS2

High Hemizygotes in GnomAdExome4 at 8 AR,XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCB	NM_001018113.3	MANE Select	c.1349G>A	p.Cys450Tyr	missense	Exon 7 of 10	NP_001018123.1	Q8NB91
FANCB	NM_001410764.1		c.1349G>A	p.Cys450Tyr	missense	Exon 7 of 13	NP_001397693.1	A0A8Q3WL66
FANCB	NM_001324162.2		c.1349G>A	p.Cys450Tyr	missense	Exon 7 of 10	NP_001311091.1	Q8NB91

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCB	ENST00000650831.1	MANE Select	c.1349G>A	p.Cys450Tyr	missense	Exon 7 of 10	ENSP00000498215.1	Q8NB91
FANCB	ENST00000324138.7	TSL:1	c.1349G>A	p.Cys450Tyr	missense	Exon 6 of 9	ENSP00000326819.3	Q8NB91
FANCB	ENST00000452869.2	TSL:1	c.1349G>A	p.Cys450Tyr	missense	Exon 7 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes

AF:

0.0000187

AC:

AN:

107008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000101

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:

0.00

Gnomad OTH

AF:

0.000703

GnomAD2 exomes

AF:

0.0000227

AC:

AN:

175901

AF XY:

0.0000652

show subpopulations

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:

0.0000385

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000162

AC:

AN:

1051701

Hom.:

Cov.:

AF XY:

0.0000247

AC XY:

AN XY:

323617

show subpopulations

African (AFR)

AF:

0.0000392

AC:

AN:

25489

American (AMR)

AF:

0.00

AC:

AN:

34723

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18935

East Asian (EAS)

AF:

0.00

AC:

AN:

29737

South Asian (SAS)

AF:

0.0000192

AC:

AN:

51973

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40155

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3966

European-Non Finnish (NFE)

AF:

0.0000175

AC:

AN:

802266

Other (OTH)

AF:

0.0000225

AC:

AN:

44457

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000187

AC:

AN:

107008

Hom.:

Cov.:

AF XY:

0.0000332

AC XY:

AN XY:

30116

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

28804

American (AMR)

AF:

0.000101

AC:

AN:

9885

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2606

East Asian (EAS)

AF:

0.00

AC:

AN:

3452

South Asian (SAS)

AF:

0.00

AC:

AN:

2502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

227

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52192

Other (OTH)

AF:

0.000703

AC:

AN:

1423

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000495

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.61

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.5

PhyloP100

2.3

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-4.1

REVEL

Benign

0.25

Sift

Benign

0.45

Sift4G

Benign

0.52

Polyphen

0.96

Vest4

0.34

MutPred

0.68

Loss of disorder (P = 0.0986)

MVP

0.44

MPC

0.57

ClinPred

0.30

GERP RS

4.7

Varity_R

0.29

Mutation Taster

=96/4

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over