Genetic Variant FANCB:c.1327-8_1327-3dupTTTTTT (chrX-14850676-T-TAAAAAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_001018113.3(FANCB):c.1327-8_1327-3dupTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 952,421 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 0.0000010 ( 0 hom. 0 hem. )

Consequence

FANCB
NM_001018113.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.476

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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	Effect	Exon Rank	Protein	UniProt
FANCB	NM_001018113.3	MANE Select	c.1327-8_1327-3dupTTTTTT	splice_region intron	N/A	NP_001018123.1	Q8NB91
FANCB	NM_001410764.1		c.1327-8_1327-3dupTTTTTT	splice_region intron	N/A	NP_001397693.1	A0A8Q3WL66
FANCB	NM_001324162.2		c.1327-8_1327-3dupTTTTTT	splice_region intron	N/A	NP_001311091.1	Q8NB91

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FANCB	ENST00000650831.1	MANE Select	c.1327-3_1327-2insTTTTTT	splice_region intron	N/A	ENSP00000498215.1	Q8NB91
FANCB	ENST00000324138.7	TSL:1	c.1327-3_1327-2insTTTTTT	splice_region intron	N/A	ENSP00000326819.3	Q8NB91
FANCB	ENST00000452869.2	TSL:1	c.1327-3_1327-2insTTTTTT	splice_region intron	N/A	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000105

AC:

AN:

952421

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

272203

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

23063

American (AMR)

AF:

0.0000329

AC:

AN:

30354

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17284

East Asian (EAS)

AF:

0.00

AC:

AN:

26277

South Asian (SAS)

AF:

0.00

AC:

AN:

45762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37815

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

727820

Other (OTH)

AF:

0.00

AC:

AN:

40460

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.48

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over