rs747865842

Positions:

• chrX-14843919-A-C
• chrX-14843919-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001018113.3(FANCB):​c.2228T>G​(p.Phe743Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000408 in 1,200,821 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 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. F743Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.0300

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.020747423).
• BP6: Variant X-14843919-A-C is Benign according to our data. Variant chrX-14843919-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 435139.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000286 (32/112008) while in subpopulation AFR AF= 0.000972 (30/30854). AF 95% confidence interval is 0.0007. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCB	NM_001018113.3	c.2228T>G	p.Phe743Cys	missense_variant	10/10	ENST00000650831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCB	ENST00000650831.1	c.2228T>G	p.Phe743Cys	missense_variant	10/10		NM_001018113.3	P2

Frequencies

GnomAD3 genomes AF: 0.000286 AC: 32 AN: 111954 Hom.: 0 Cov.: 23 AF XY: 0.000176 AC XY: 6 AN XY: 34110

Gnomad AFR AF: 0.000975

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

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: 0.000661

GnomAD3 exomes AF: 0.0000781 AC: 14 AN: 179232 Hom.: 0 AF XY: 0.0000621 AC XY: 4 AN XY: 64442

Gnomad AFR exome AF: 0.000855

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 17 AN: 1088813 Hom.: 0 Cov.: 28 AF XY: 0.0000113 AC XY: 4 AN XY: 354785

Gnomad4 AFR exome AF: 0.000574

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000120

Gnomad4 OTH exome AF: 0.0000219

GnomAD4 genome AF: 0.000286 AC: 32 AN: 112008 Hom.: 0 Cov.: 23 AF XY: 0.000176 AC XY: 6 AN XY: 34174

Gnomad4 AFR AF: 0.000972

Gnomad4 AMR AF: 0.0000948

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000653

Alfa AF: 0.000174 Hom.: 0

Bravo AF: 0.000298

ExAC AF: 0.0000824 AC: 10

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 31, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 24, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 07, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.8
DANN	Benign	0.83
DEOGEN2	Benign	0.17	T;T;T
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.67	T;.;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.056
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.91	P;P;.
Vest4		0.15
MVP		0.15
MPC		0.15
ClinPred		0.14	T
GERP RS		1.9
Varity_R		0.12

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

LitVar

Other links and lift over

dbSNP: rs747865842; hg19: chrX-14862041;