rs41309679

Variant names:

• chrX-14859282-C-T
• rs41309679
• NM_001018113.3:c.1004G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018113.3(FANCB):​c.1004G>A​(p.Gly335Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0731 in 1,187,007 control chromosomes in the GnomAD database, including 2,526 homozygotes. There are 27,854 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G335V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.054 (155 hom., 1766 hem., cov: 23)
  • Exomes 𝑓: 0.075 (2371 hom. 26088 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.56
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026280582).
• BP6: Variant X-14859282-C-T is Benign according to our data. Variant chrX-14859282-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

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.1004G>A	p.Gly335Glu	missense	Exon 4 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1004G>A	p.Gly335Glu	missense	Exon 4 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1004G>A	p.Gly335Glu	missense	Exon 4 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.1004G>A	p.Gly335Glu	missense	Exon 4 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1004G>A	p.Gly335Glu	missense	Exon 3 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1004G>A	p.Gly335Glu	missense	Exon 4 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 6078 AN: 111377 Hom.: 156 Cov.: 23

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00872

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0684

Gnomad NFE AF: 0.0816

Gnomad OTH AF: 0.0674

GnomAD2 exomes AF: 0.0617 AC: 11246 AN: 182122 AF XY: 0.0656

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0256

Gnomad ASJ exome AF: 0.0896

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.0775

Gnomad NFE exome AF: 0.0843

Gnomad OTH exome AF: 0.0667

GnomAD4 exome AF: 0.0750 AC: 80647 AN: 1075579 Hom.: 2371 Cov.: 25 AF XY: 0.0758 AC XY: 26088 AN XY: 344073

African (AFR) AF: 0.00980 AC: 255 AN: 26011

American (AMR) AF: 0.0287 AC: 1007 AN: 35095

Ashkenazi Jewish (ASJ) AF: 0.0928 AC: 1781 AN: 19186

East Asian (EAS) AF: 0.000434 AC: 13 AN: 29980

South Asian (SAS) AF: 0.0782 AC: 4183 AN: 53457

European-Finnish (FIN) AF: 0.0808 AC: 3273 AN: 40491

Middle Eastern (MID) AF: 0.0750 AC: 305 AN: 4065

European-Non Finnish (NFE) AF: 0.0812 AC: 66743 AN: 821991

Other (OTH) AF: 0.0681 AC: 3087 AN: 45303

GnomAD4 genome AF: 0.0545 AC: 6072 AN: 111428 Hom.: 155 Cov.: 23 AF XY: 0.0524 AC XY: 1766 AN XY: 33686

African (AFR) AF: 0.0101 AC: 312 AN: 30808

American (AMR) AF: 0.0405 AC: 425 AN: 10484

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 276 AN: 2637

East Asian (EAS) AF: 0.000563 AC: 2 AN: 3553

South Asian (SAS) AF: 0.0615 AC: 165 AN: 2682

European-Finnish (FIN) AF: 0.0763 AC: 448 AN: 5873

Middle Eastern (MID) AF: 0.0563 AC: 12 AN: 213

European-Non Finnish (NFE) AF: 0.0816 AC: 4325 AN: 52972

Other (OTH) AF: 0.0665 AC: 101 AN: 1518

Alfa AF: 0.0760 Hom.: 4039

Bravo AF: 0.0510

TwinsUK AF: 0.0863 AC: 320

ALSPAC AF: 0.0723 AC: 209

ESP6500AA AF: 0.0149 AC: 57

ESP6500EA AF: 0.0842 AC: 566

ExAC AF: 0.0663 AC: 8054

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group B (4)
-	-	2	Fanconi anemia (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		4.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.58
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.85
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs41309679; hg19: chrX-14877404;