NM_001018113.3:c.510T>G

Variant names:

• chrX-14865001-A-C
• rs775216604
• NM_001018113.3:c.510T>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001018113.3(FANCB):​c.510T>G​(p.Ile170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,209,182 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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. I170L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000046 (0 hom. 17 hem.)
• Consequence: FANCB NM_001018113.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.168
• 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: 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07617468).
• BP6: Variant X-14865001-A-C is Benign according to our data. Variant chrX-14865001-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 408161.
• BS2: High Hemizygotes in GnomAdExome4 at 17 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.510T>G	p.Ile170Met	missense	Exon 3 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.510T>G	p.Ile170Met	missense	Exon 3 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.510T>G	p.Ile170Met	missense	Exon 3 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.510T>G	p.Ile170Met	missense	Exon 3 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.510T>G	p.Ile170Met	missense	Exon 2 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.510T>G	p.Ile170Met	missense	Exon 3 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111442 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 8 AN: 183104 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000979

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000465 AC: 51 AN: 1097740 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 17 AN XY: 363142

African (AFR) AF: 0.00 AC: 0 AN: 26392

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30186

South Asian (SAS) AF: 0.00 AC: 0 AN: 54103

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 841745

Other (OTH) AF: 0.0000868 AC: 4 AN: 46084

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111442 Hom.: 0 Cov.: 24 AF XY: 0.0000297 AC XY: 1 AN XY: 33628

African (AFR) AF: 0.00 AC: 0 AN: 30686

American (AMR) AF: 0.00 AC: 0 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3561

South Asian (SAS) AF: 0.00 AC: 0 AN: 2660

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5965

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000566 AC: 3 AN: 53044

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.000174 Hom.: 2

Bravo AF: 0.0000151

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Fanconi anemia (1)
-	-	1	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.17
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.042
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.99	D
Vest4		0.25
MutPred		0.27		Gain of helix (P = 0.062)
MVP		0.25
MPC		0.48
ClinPred		0.19	T
GERP RS		2.7
Varity_R		0.31
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: rs775216604; hg19: chrX-14883123;