chrX-14859297-A-G

Variant names:

• chrX-14859297-A-G
• rs200161949
• NM_001018113.3:c.989T>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.989T>C​(p.Ile330Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000576 in 1,191,371 control chromosomes in the GnomAD database, including 1 homozygotes. There are 217 hemizygotes in GnomAD. In-silico tool predicts 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. I330V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00059 (1 hom. 206 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: 5.66
• Publications: 4 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=0.028166264).
• BP6: Variant X-14859297-A-G is Benign according to our data. Variant chrX-14859297-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197175.
• BS2: High Hemizygotes in GnomAd4 at 11 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.989T>C	p.Ile330Thr	missense	Exon 4 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.989T>C	p.Ile330Thr	missense	Exon 4 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.989T>C	p.Ile330Thr	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.989T>C	p.Ile330Thr	missense	Exon 4 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.989T>C	p.Ile330Thr	missense	Exon 3 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.989T>C	p.Ile330Thr	missense	Exon 4 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.000474 AC: 53 AN: 111825 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000649

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000377

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000640

Gnomad OTH AF: 0.00200

GnomAD2 exomes AF: 0.000504 AC: 92 AN: 182720 AF XY: 0.000490

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00158

Gnomad ASJ exome AF: 0.000268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000490

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000586 AC: 633 AN: 1079495 Hom.: 1 Cov.: 26 AF XY: 0.000594 AC XY: 206 AN XY: 346783

African (AFR) AF: 0.0000767 AC: 2 AN: 26067

American (AMR) AF: 0.00159 AC: 56 AN: 35126

Ashkenazi Jewish (ASJ) AF: 0.000208 AC: 4 AN: 19227

East Asian (EAS) AF: 0.00 AC: 0 AN: 30001

South Asian (SAS) AF: 0.00 AC: 0 AN: 53572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40501

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4079

European-Non Finnish (NFE) AF: 0.000652 AC: 538 AN: 825482

Other (OTH) AF: 0.000704 AC: 32 AN: 45440

GnomAD4 genome AF: 0.000474 AC: 53 AN: 111876 Hom.: 0 Cov.: 23 AF XY: 0.000323 AC XY: 11 AN XY: 34048

African (AFR) AF: 0.0000648 AC: 2 AN: 30880

American (AMR) AF: 0.00124 AC: 13 AN: 10516

Ashkenazi Jewish (ASJ) AF: 0.000377 AC: 1 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5999

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.000640 AC: 34 AN: 53131

Other (OTH) AF: 0.00197 AC: 3 AN: 1522

Alfa AF: 0.000520 Hom.: 21

Bravo AF: 0.000695

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000453 AC: 55

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	not provided (5)
-	-	2	Fanconi anemia (2)
-	-	2	not specified (2)
-	-	1	FANCB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Uncertain	0.45	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.7
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.26
Sift	Benign	0.10	T
Sift4G	Uncertain	0.0090	D
Polyphen		0.11	B
Vest4		0.53
MVP		0.61
MPC		0.32
ClinPred		0.032	T
GERP RS		5.8
Varity_R		0.27
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs200161949; hg19: chrX-14877419;