NM_001018113.3:c.1327-3dupT

Variant names:

• chrX-14850676-T-TA
• rs202067682
• NM_001018113.3:c.1327-3dupT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_001018113.3(FANCB):​c.1327-3dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000825 in 1,045,956 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., 3 hem., cov: 21)
  • Exomes 𝑓: 0.00091 (0 hom. 12 hem.)
• Consequence: FANCB NM_001018113.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.476
• 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: 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: Benign. The variant received -12 ACMG points.

• BP6: Variant X-14850676-T-TA is Benign according to our data. Variant chrX-14850676-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1169946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	NM_001018113.3	MANE Select	c.1327-3dupT		splice_region intron	N/A	NP_001018123.1
	FANCB	NM_001410764.1		c.1327-3dupT		splice_region intron	N/A	NP_001397693.1
	FANCB	NM_001324162.2		c.1327-3dupT		splice_region intron	N/A	NP_001311091.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCB	ENST00000650831.1	MANE Select	c.1327-3_1327-2insT		splice_region intron	N/A	ENSP00000498215.1
	FANCB	ENST00000324138.7	TSL:1	c.1327-3_1327-2insT		splice_region intron	N/A	ENSP00000326819.3
	FANCB	ENST00000452869.2	TSL:1	c.1327-3_1327-2insT		splice_region intron	N/A	ENSP00000397849.2

Frequencies

GnomAD3 genomes AF: 0.0000853 AC: 9 AN: 105514 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000103

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000594

Gnomad SAS AF: 0.00162

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000195

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000591 AC: 74 AN: 125253 AF XY: 0.000112

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00138

Gnomad ASJ exome AF: 0.000375

Gnomad EAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000313

Gnomad NFE exome AF: 0.000312

Gnomad OTH exome AF: 0.000634

GnomAD4 exome AF: 0.000908 AC: 854 AN: 940414 Hom.: 0 Cov.: 19 AF XY: 0.0000452 AC XY: 12 AN XY: 265734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000526 AC: 12 AN: 22797

American (AMR) AF: 0.000738 AC: 22 AN: 29820

Ashkenazi Jewish (ASJ) AF: 0.000527 AC: 9 AN: 17063

East Asian (EAS) AF: 0.000553 AC: 14 AN: 25337

South Asian (SAS) AF: 0.00162 AC: 72 AN: 44469

European-Finnish (FIN) AF: 0.000107 AC: 4 AN: 37496

Middle Eastern (MID) AF: 0.000563 AC: 2 AN: 3551

European-Non Finnish (NFE) AF: 0.000964 AC: 694 AN: 719971

Other (OTH) AF: 0.000626 AC: 25 AN: 39910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000853 AC: 9 AN: 105542 Hom.: 0 Cov.: 21 AF XY: 0.000101 AC XY: 3 AN XY: 29666

African (AFR) AF: 0.0000346 AC: 1 AN: 28881

American (AMR) AF: 0.000103 AC: 1 AN: 9716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2570

East Asian (EAS) AF: 0.000596 AC: 2 AN: 3355

South Asian (SAS) AF: 0.00163 AC: 4 AN: 2451

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5005

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 206

European-Non Finnish (NFE) AF: 0.0000195 AC: 1 AN: 51277

Other (OTH) AF: 0.00 AC: 0 AN: 1412

Alfa AF: 0.00423 Hom.: 27

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia Benign:2

Jun 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 17, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

not specified Benign:1

Aug 24, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.48
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs202067682; hg19: chrX-14868798;