rs577636020

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS3

The NM_000135.4(FANCA):c.2602-9_2602-8delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004848901: RT-PCR analysis lymphoblastoid cell lines derived from one of the Fanconi anemia patients suggests that the variant results in aberrant splicing, and thus would be expected to lead to a truncated or absent protein. PMID:29098742".

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

FANCA
NM_000135.4 splice_region, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:10B:1

Conservation

PhyloP100: 0.996

Publications

2 publications found

Variant links:

COSMIC-nc: COSV59798201

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

FANCA Gene-Disease associations (from GenCC):

Fanconi anemia complementation group A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV004848901: RT-PCR analysis lymphoblastoid cell lines derived from one of the Fanconi anemia patients suggests that the variant results in aberrant splicing, and thus would be expected to lead to a truncated or absent protein. PMID:29098742

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. 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
	FANCA	NM_000135.4	MANE Select	c.2602-9_2602-8delCT		splice_region intron	N/A	NP_000126.2	O15360-1
	FANCA	NM_001286167.3		c.2602-9_2602-8delCT		splice_region intron	N/A	NP_001273096.1	O15360-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FANCA	ENST00000389301.8	TSL:1 MANE Select	c.2602-9_2602-8delCT	splice_region intron	N/A	ENSP00000373952.3	O15360-1
FANCA	ENST00000564475.6	TSL:2	c.2602-9_2602-8delCT	splice_region intron	N/A	ENSP00000454977.2	H3BNS0
FANCA	ENST00000568369.6	TSL:2	c.2602-9_2602-8delCT	splice_region intron	N/A	ENSP00000456829.1	O15360-3

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000713

AC:

179

AN:

251154

AF XY:

0.000707

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00171

Gnomad NFE exome

AF:

0.000864

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000585

AC:

855

AN:

1461596

Hom.:

AF XY:

0.000589

AC XY:

428

AN XY:

727090

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33476

American (AMR)

AF:

0.0000671

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.000612

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00103

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.00210

AC:

112

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000532

AC:

592

AN:

1111840

Other (OTH)

AF:

0.000596

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000434

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41460

American (AMR)

AF:

0.000262

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68038

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000654

Hom.:

Bravo

AF:

0.000400

EpiCase

AF:

0.00104

EpiControl

AF:

0.000474

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia (4)

Fanconi anemia complementation group A (4)

not provided (3)

not specified (2)

FANCA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.0

Mutation Taster

=26/74

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.25

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.25

Position offset: -7

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over