rs201436396

Variant names:

• chrX-14843670-G-A
• rs201436396
• NM_001018113.3:c.2477C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-14843670-G-A
• chrX-14843670-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001018113.3(FANCB):​c.2477C>T​(p.Thr826Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,207,512 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 121 hemizygotes 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T826K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., 10 hem., cov: 23)
  • Exomes 𝑓: 0.00031 (0 hom. 111 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.349
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068685114).
• BP6: Variant X-14843670-G-A is Benign according to our data. Variant chrX-14843670-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 414827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 10 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.2477C>T	p.Thr826Met	missense	Exon 10 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.2477C>T	p.Thr826Met	missense	Exon 10 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.2477C>T	p.Thr826Met	missense	Exon 10 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.2477C>T	p.Thr826Met	missense	Exon 10 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.2477C>T	p.Thr826Met	missense	Exon 9 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.2477C>T	p.Thr826Met	missense	Exon 10 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.000314 AC: 35 AN: 111488 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000191

Gnomad ASJ AF: 0.00303

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000370

Gnomad FIN AF: 0.000334

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000396

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000334 AC: 61 AN: 182654 AF XY: 0.000312

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00201

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000626

Gnomad NFE exome AF: 0.000492

Gnomad OTH exome AF: 0.000444

GnomAD4 exome AF: 0.000307 AC: 336 AN: 1096024 Hom.: 0 Cov.: 29 AF XY: 0.000307 AC XY: 111 AN XY: 361444

African (AFR) AF: 0.0000759 AC: 2 AN: 26354

American (AMR) AF: 0.0000284 AC: 1 AN: 35185

Ashkenazi Jewish (ASJ) AF: 0.00284 AC: 55 AN: 19351

East Asian (EAS) AF: 0.00 AC: 0 AN: 30182

South Asian (SAS) AF: 0.000111 AC: 6 AN: 54054

European-Finnish (FIN) AF: 0.000123 AC: 5 AN: 40519

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.000296 AC: 249 AN: 840236

Other (OTH) AF: 0.000391 AC: 18 AN: 46014

GnomAD4 genome AF: 0.000314 AC: 35 AN: 111488 Hom.: 0 Cov.: 23 AF XY: 0.000297 AC XY: 10 AN XY: 33704

African (AFR) AF: 0.0000326 AC: 1 AN: 30679

American (AMR) AF: 0.000191 AC: 2 AN: 10455

Ashkenazi Jewish (ASJ) AF: 0.00303 AC: 8 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3555

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2706

European-Finnish (FIN) AF: 0.000334 AC: 2 AN: 5996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000396 AC: 21 AN: 53055

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.000714 Hom.: 42

Bravo AF: 0.000329

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000656

EpiControl AF: 0.000297

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia (2)
-	-	2	Fanconi anemia complementation group B (2)
-	-	1	FANCB-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.0010
DANN	Benign	0.046
DEOGEN2	Benign	0.053	T
FATHMM_MKL	Benign	0.0050	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.42	N
PhyloP100		-0.35
PrimateAI	Benign	0.22	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.045
Sift	Benign	0.65	T
Sift4G	Benign	0.24	T
Polyphen		0.042	B
Vest4		0.011
MVP		0.082
MPC		0.10
ClinPred		0.0099	T
GERP RS		-6.3
Varity_R		0.016
Mutation Taster		=100/0	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: rs201436396; hg19: chrX-14861792;