rs1555904458

Variant names:

• chrX-14845178-G-C
• rs1555904458
• NM_001018113.3:c.1605C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001018113.3(FANCB):​c.1605C>G​(p.Phe535Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0300
• Publications: 0 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: G2P, ClinGen, 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.039045244).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	NM_001018113.3	MANE Select	c.1605C>G	p.Phe535Leu	missense	Exon 8 of 10	NP_001018123.1
	FANCB	NM_001410764.1		c.1605C>G	p.Phe535Leu	missense	Exon 8 of 13	NP_001397693.1
	FANCB	NM_001324162.2		c.1605C>G	p.Phe535Leu	missense	Exon 8 of 10	NP_001311091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.1605C>G	p.Phe535Leu	missense	Exon 8 of 10	ENSP00000498215.1
	FANCB	ENST00000324138.7	TSL:1	c.1605C>G	p.Phe535Leu	missense	Exon 7 of 9	ENSP00000326819.3
	FANCB	ENST00000452869.2	TSL:1	c.1605C>G	p.Phe535Leu	missense	Exon 8 of 11	ENSP00000397849.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.12
DANN	Benign	0.50
DEOGEN2	Benign	0.094	T
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.30	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.43	N
PhyloP100		-0.030
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	0.72	T
Polyphen		0.021	B
Vest4		0.060
MutPred		0.29		Gain of glycosylation at P538 (P = 0.1277)
MVP		0.10
MPC		0.12
ClinPred		0.044	T
GERP RS		-4.0
Varity_R		0.048
Mutation Taster		=93/7	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: rs1555904458; hg19: chrX-14863300;