rs199510538

Variant names:

• chrX-14850507-C-A
• rs199510538
• NM_001018113.3:c.1494G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-14850507-C-A
• chrX-14850507-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001018113.3(FANCB):​c.1494G>T​(p.Lys498Asn) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,196,527 control chromosomes in the GnomAD database, including 15 homozygotes. There are 778 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (1 hom., 42 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (14 hom. 736 hem.)
• Consequence: FANCB NM_001018113.3 missense, splice_region
• Scores: Splicing: ADA: 0.0006412
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 0.0720
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028890371).
• BP6: Variant X-14850507-C-A is Benign according to our data. Variant chrX-14850507-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 368024.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000653 (73/111866) while in subpopulation SAS AF = 0.027 (73/2708). AF 95% confidence interval is 0.022. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 42 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.1494G>T	p.Lys498Asn	missense splice_region	Exon 7 of 10	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1494G>T	p.Lys498Asn	missense splice_region	Exon 7 of 13	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1494G>T	p.Lys498Asn	missense splice_region	Exon 7 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.1494G>T	p.Lys498Asn	missense splice_region	Exon 7 of 10	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1494G>T	p.Lys498Asn	missense splice_region	Exon 6 of 9	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1494G>T	p.Lys498Asn	missense splice_region	Exon 7 of 11	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 72 AN: 111815 Hom.: 1 Cov.: 23

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: 0.0265

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00252 AC: 463 AN: 183378 AF XY: 0.00410

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00121 AC: 1308 AN: 1084661 Hom.: 14 Cov.: 27 AF XY: 0.00209 AC XY: 736 AN XY: 351375

African (AFR) AF: 0.0000765 AC: 2 AN: 26152

American (AMR) AF: 0.0000568 AC: 2 AN: 35184

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19307

East Asian (EAS) AF: 0.00 AC: 0 AN: 30111

South Asian (SAS) AF: 0.0231 AC: 1241 AN: 53829

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

Middle Eastern (MID) AF: 0.000751 AC: 3 AN: 3994

European-Non Finnish (NFE) AF: 0.00000482 AC: 4 AN: 829979

Other (OTH) AF: 0.00123 AC: 56 AN: 45604

GnomAD4 genome AF: 0.000653 AC: 73 AN: 111866 Hom.: 1 Cov.: 23 AF XY: 0.00123 AC XY: 42 AN XY: 34058

African (AFR) AF: 0.00 AC: 0 AN: 30800

American (AMR) AF: 0.00 AC: 0 AN: 10564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.0270 AC: 73 AN: 2708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5989

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53159

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.00320 AC: 389

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Fanconi anemia (2)
-	-	2	Fanconi anemia complementation group B (2)
-	-	1	Fanconi anemia complementation group B;C2931228:VACTERL association, X-linked, with or without hydrocephalus (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	-	1	VACTERL association, X-linked, with or without hydrocephalus (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.072
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.37	T
Sift4G	Benign	0.084	T
Polyphen		0.92	P
Vest4		0.049
MutPred		0.23		Loss of ubiquitination at K498 (P = 0.0174)
MVP		0.31
MPC		0.13
ClinPred		0.039	T
GERP RS		2.7
Varity_R		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00064
dbscSNV1_RF	Benign	0.054
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: rs199510538; hg19: chrX-14868629;