Genetic Variant FANCB:c.1327-3dupT (chrX-14850676-T-TA) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_001018113.3(FANCB):c.1327-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000825 in 1,045,956 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.00091 ( 0 hom. 12 hem. )

Consequence

FANCB
NM_001018113.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.476

Publications

2 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: G2P, ClinGen, 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

FANCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant X-14850676-T-TA is Benign according to our data. Variant chrX-14850676-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1169946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 3 AR,XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCB	NM_001018113.3 link	c.1327-3dupT		splice_region_variant, intron_variant	Intron 6 of 9	ENST00000650831.1	NP_001018123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCB	ENST00000650831.1 link	c.1327-3_1327-2insT		splice_region_variant, intron_variant	Intron 6 of 9		NM_001018113.3	ENSP00000498215.1

Frequencies

GnomAD3 genomes

AF:

0.0000853

AC:

AN:

105514

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000103

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000594

Gnomad SAS

AF:

0.00162

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000195

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000591

AC:

AN:

125253

AF XY:

0.000112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00138

Gnomad ASJ exome

AF:

0.000375

Gnomad EAS exome

AF:

0.00106

Gnomad FIN exome

AF:

0.000313

Gnomad NFE exome

AF:

0.000312

Gnomad OTH exome

AF:

0.000634

GnomAD4 exome

AF:

0.000908

AC:

854

AN:

940414

Hom.:

Cov.:

AF XY:

0.0000452

AC XY:

AN XY:

265734

show subpopulations

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

African (AFR)

AF:

0.000526

AC:

AN:

22797

American (AMR)

AF:

0.000738

AC:

AN:

29820

Ashkenazi Jewish (ASJ)

AF:

0.000527

AC:

AN:

17063

East Asian (EAS)

AF:

0.000553

AC:

AN:

25337

South Asian (SAS)

AF:

0.00162

AC:

AN:

44469

European-Finnish (FIN)

AF:

0.000107

AC:

AN:

37496

Middle Eastern (MID)

AF:

0.000563

AC:

AN:

3551

European-Non Finnish (NFE)

AF:

0.000964

AC:

694

AN:

719971

Other (OTH)

AF:

0.000626

AC:

AN:

39910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 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: 0.248

Heterozygous variant carriers

134

268

402

536

670

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.0000853

AC:

AN:

105542

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

29666

show subpopulations

African (AFR)

AF:

0.0000346

AC:

AN:

28881

American (AMR)

AF:

0.000103

AC:

AN:

9716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2570

East Asian (EAS)

AF:

0.000596

AC:

AN:

3355

South Asian (SAS)

AF:

0.00163

AC:

AN:

2451

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5005

Middle Eastern (MID)

AF:

0.00

AC:

AN:

206

European-Non Finnish (NFE)

AF:

0.0000195

AC:

AN:

51277

Other (OTH)

AF:

0.00

AC:

AN:

1412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.00423

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia

Benign:2

Jun 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 17, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

not specified

Benign:1

Aug 24, 2021

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.48

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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X-14850676-TAAA-TAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over