X-14845014-A-G

Variant names:

• chrX-14845014-A-G
• rs142959373
• NM_001018113.3:c.1769T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001018113.3(FANCB):​c.1769T>C​(p.Phe590Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0015 in 1,208,655 control chromosomes in the GnomAD database, including 5 homozygotes. There are 649 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 40 hem., cov: 23)
  • Exomes 𝑓: 0.0015 (5 hom. 609 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 5.04
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004327774).
• BP6: Variant X-14845014-A-G is Benign according to our data. Variant chrX-14845014-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 246611.
• BS2: High Hemizygotes in GnomAd4 at 40 AR,XL gene

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.1769T>C	p.Phe590Ser	missense	Exon 8 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1769T>C	p.Phe590Ser	missense	Exon 8 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1769T>C	p.Phe590Ser	missense	Exon 8 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.1769T>C	p.Phe590Ser	missense	Exon 8 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1769T>C	p.Phe590Ser	missense	Exon 7 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1769T>C	p.Phe590Ser	missense	Exon 8 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 124 AN: 112170 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000472

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.000665

GnomAD2 exomes AF: 0.00158 AC: 289 AN: 182657 AF XY: 0.00183

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000439

Gnomad ASJ exome AF: 0.0147

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.00289

GnomAD4 exome AF: 0.00154 AC: 1684 AN: 1096433 Hom.: 5 Cov.: 30 AF XY: 0.00168 AC XY: 609 AN XY: 361935

African (AFR) AF: 0.000190 AC: 5 AN: 26357

American (AMR) AF: 0.000313 AC: 11 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.0129 AC: 250 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00248 AC: 134 AN: 54041

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00339 AC: 14 AN: 4128

European-Non Finnish (NFE) AF: 0.00140 AC: 1175 AN: 840677

Other (OTH) AF: 0.00206 AC: 95 AN: 46030

GnomAD4 genome AF: 0.00110 AC: 124 AN: 112222 Hom.: 0 Cov.: 23 AF XY: 0.00116 AC XY: 40 AN XY: 34408

African (AFR) AF: 0.0000970 AC: 3 AN: 30942

American (AMR) AF: 0.000472 AC: 5 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 38 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3574

South Asian (SAS) AF: 0.00146 AC: 4 AN: 2733

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6073

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00135 AC: 72 AN: 53229

Other (OTH) AF: 0.000657 AC: 1 AN: 1522

Alfa AF: 0.00202 Hom.: 101

Bravo AF: 0.00109

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 3

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00163 AC: 11

ExAC AF: 0.00129 AC: 157

EpiCase AF: 0.00191

EpiControl AF: 0.00160

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Fanconi anemia complementation group B (2)
-	-	2	not specified (2)
-	-	1	FANCB-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group A (1)
-	1	-	History of neurodevelopmental disorder (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.0
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.21
Sift	Benign	0.052	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.18	B
Vest4		0.20
MVP		0.57
MPC		0.25
ClinPred		0.028	T
GERP RS		4.3
Varity_R		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs142959373; hg19: chrX-14863136;