chrX-14857956-T-TAATA

Variant names:

• chrX-14857956-T-TAATA
• rs398123537
• NM_001018113.3:c.1105-6_1105-3dupTATT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001018113.3(FANCB):​c.1105-6_1105-3dupTATT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00259 in 1,065,970 control chromosomes in the GnomAD database, including 25 homozygotes. There are 597 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (19 hom., 246 hem., cov: 22)
  • Exomes 𝑓: 0.0018 (6 hom. 351 hem.)
• Consequence: FANCB NM_001018113.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.218
• Publications: 2 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.

• BP6: Variant X-14857956-T-TAATA is Benign according to our data. Variant chrX-14857956-T-TAATA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167060.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00976 (1091/111735) while in subpopulation AFR AF = 0.0307 (942/30696). AF 95% confidence interval is 0.0291. There are 19 homozygotes in GnomAd4. There are 246 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.1105-6_1105-3dupTATT		splice_region intron	N/A	NP_001018123.1	Q8NB91
	FANCB	NM_001410764.1		c.1105-6_1105-3dupTATT		splice_region intron	N/A	NP_001397693.1	A0A8Q3WL66
	FANCB	NM_001324162.2		c.1105-6_1105-3dupTATT		splice_region intron	N/A	NP_001311091.1	Q8NB91

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.1105-3_1105-2insTATT		splice_region intron	N/A	ENSP00000498215.1	Q8NB91
	FANCB	ENST00000324138.7	TSL:1	c.1105-3_1105-2insTATT		splice_region intron	N/A	ENSP00000326819.3	Q8NB91
	FANCB	ENST00000452869.2	TSL:1	c.1105-3_1105-2insTATT		splice_region intron	N/A	ENSP00000397849.2	C9J5X9

Frequencies

GnomAD3 genomes AF: 0.00975 AC: 1089 AN: 111688 Hom.: 19 Cov.: 22

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00372

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00139

Gnomad SAS AF: 0.000727

Gnomad FIN AF: 0.000668

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00801

GnomAD2 exomes AF: 0.00250 AC: 444 AN: 177339 AF XY: 0.00117

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.00201

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000814

Gnomad FIN exome AF: 0.000126

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.000689

GnomAD4 exome AF: 0.00175 AC: 1670 AN: 954235 Hom.: 6 Cov.: 17 AF XY: 0.00132 AC XY: 351 AN XY: 266053

African (AFR) AF: 0.0220 AC: 511 AN: 23277

American (AMR) AF: 0.00230 AC: 79 AN: 34354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18277

East Asian (EAS) AF: 0.000238 AC: 7 AN: 29460

South Asian (SAS) AF: 0.000323 AC: 16 AN: 49558

European-Finnish (FIN) AF: 0.000274 AC: 11 AN: 40163

Middle Eastern (MID) AF: 0.00285 AC: 9 AN: 3154

European-Non Finnish (NFE) AF: 0.00125 AC: 891 AN: 714726

Other (OTH) AF: 0.00354 AC: 146 AN: 41266

GnomAD4 genome AF: 0.00976 AC: 1091 AN: 111735 Hom.: 19 Cov.: 22 AF XY: 0.00723 AC XY: 246 AN XY: 34003

African (AFR) AF: 0.0307 AC: 942 AN: 30696

American (AMR) AF: 0.00372 AC: 39 AN: 10491

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00140 AC: 5 AN: 3583

South Asian (SAS) AF: 0.000729 AC: 2 AN: 2742

European-Finnish (FIN) AF: 0.000668 AC: 4 AN: 5985

Middle Eastern (MID) AF: 0.00461 AC: 1 AN: 217

European-Non Finnish (NFE) AF: 0.00162 AC: 86 AN: 53173

Other (OTH) AF: 0.00792 AC: 12 AN: 1516

Alfa AF: 0.00113 Hom.: 5

Bravo AF: 0.0119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia (2)
-	-	2	not specified (2)
-	-	1	Fanconi anemia complementation group B (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.22
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398123537; hg19: chrX-14876078;