rs773159223

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000135.4(FANCA):c.154C>T(p.Arg52*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000016 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCA
NM_000135.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 1.12

Publications

4 publications found

Variant links:

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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-89815912-G-A is Pathogenic according to our data. Variant chr16-89815912-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 371668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCA	NM_000135.4	MANE Select	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 43	NP_000126.2	O15360-1
FANCA	NM_001286167.3		c.154C>T	p.Arg52*	stop_gained	Exon 2 of 43	NP_001273096.1	O15360-3
FANCA	NM_001018112.3		c.154C>T	p.Arg52*	stop_gained	Exon 2 of 11	NP_001018122.1	O15360-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCA	ENST00000389301.8	TSL:1 MANE Select	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 43	ENSP00000373952.3	O15360-1
FANCA	ENST00000563673.5	TSL:1	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 10	ENSP00000456443.1	H3BRX3
FANCA	ENST00000534992.5	TSL:1	c.154C>T	p.Arg52*	stop_gained	Exon 2 of 11	ENSP00000443675.1	F5H8D5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152234

Hom.:

Cov.:

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251492

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461742

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111902

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74372

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68040

Other (OTH)

AF:

0.00

AC:

AN:

2092

Alfa

AF:

0.0000431

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia (3)

Fanconi anemia complementation group A (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.20

PhyloP100

1.1

Vest4

0.88

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over