chrX-14850659-G-T

Variant names:

• chrX-14850659-G-T
• rs867778700
• NM_001018113.3:c.1342C>A

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.1342C>A​(p.Pro448Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 107,540 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/19 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. P448S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000093 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.33
• 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=0.09276673).

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.1342C>A	p.Pro448Thr	missense	Exon 7 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1342C>A	p.Pro448Thr	missense	Exon 7 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1342C>A	p.Pro448Thr	missense	Exon 7 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.1342C>A	p.Pro448Thr	missense	Exon 7 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1342C>A	p.Pro448Thr	missense	Exon 6 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1342C>A	p.Pro448Thr	missense	Exon 7 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.00000930 AC: 1 AN: 107540 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000191

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1047338 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 320170

African (AFR) AF: 0.00 AC: 0 AN: 25376

American (AMR) AF: 0.00 AC: 0 AN: 34614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18875

East Asian (EAS) AF: 0.00 AC: 0 AN: 29730

South Asian (SAS) AF: 0.00 AC: 0 AN: 51721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 798682

Other (OTH) AF: 0.00 AC: 0 AN: 44296

GnomAD4 genome AF: 0.00000930 AC: 1 AN: 107540 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 30446

African (AFR) AF: 0.00 AC: 0 AN: 28900

American (AMR) AF: 0.00 AC: 0 AN: 10097

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2612

East Asian (EAS) AF: 0.00 AC: 0 AN: 3466

South Asian (SAS) AF: 0.00 AC: 0 AN: 2535

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5319

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 234

European-Non Finnish (NFE) AF: 0.0000191 AC: 1 AN: 52280

Other (OTH) AF: 0.00 AC: 0 AN: 1427

Alfa AF: 0.0000843 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.4
DANN	Benign	0.11
DEOGEN2	Benign	0.11	T
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.35	N
PhyloP100		2.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.055
Sift	Benign	0.47	T
Sift4G	Benign	0.95	T
Polyphen		0.0090	B
Vest4		0.21
MutPred		0.40		Gain of sheet (P = 0.0344)
MVP		0.13
MPC		0.12
ClinPred		0.074	T
GERP RS		2.0
Varity_R		0.062
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs867778700; hg19: chrX-14868781;