NM_000136.3:c.584A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000136.3(FANCC):c.584A>T(p.Asp195Val) variant causes a missense change. The variant allele was found at a frequency of 0.00394 in 1,614,040 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 25 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:23O:1

Conservation

PhyloP100: 4.53

Publications

25 publications found

Variant links:

Genes affected

FANCC (HGNC:3584): (FA complementation group C) 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 C. [provided by RefSeq, Jul 2008]

FANCC links:

AOPEP (HGNC:1361): (aminopeptidase O (putative)) This gene encodes a member of the M1 zinc aminopeptidase family. The encoded protein is a zinc-dependent metallopeptidase that catalyzes the removal of an amino acid from the amino terminus of a protein or peptide. This protein may play a role in the generation of angiotensin IV. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Oct 2010]

AOPEP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027212769).

BP6

Variant 9-95150025-T-A is Benign according to our data. Variant chr9-95150025-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134305.

BS2

High Homozygotes in GnomAdExome4 at 25 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000136.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	NM_000136.3	MANE Select	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	NP_000127.2	Q00597
FANCC	NM_001243743.2		c.584A>T	p.Asp195Val	missense	Exon 7 of 15	NP_001230672.1	A0A024R9N2
FANCC	NM_001243744.2		c.584A>T	p.Asp195Val	missense	Exon 7 of 14	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCC	ENST00000289081.8	TSL:1 MANE Select	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	ENSP00000289081.3	Q00597
FANCC	ENST00000375305.6	TSL:1	c.584A>T	p.Asp195Val	missense	Exon 7 of 15	ENSP00000364454.1	Q00597
FANCC	ENST00000490972.7	TSL:1	c.584A>T	p.Asp195Val	missense	Exon 7 of 14	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes

AF:

0.00286

AC:

435

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000755

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00469

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00313

AC:

787

AN:

251330

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00263

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00464

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00406

AC:

5932

AN:

1461858

Hom.:

Cov.:

AF XY:

0.00413

AC XY:

3002

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

33480

American (AMR)

AF:

0.00280

AC:

125

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00344

AC:

297

AN:

86246

European-Finnish (FIN)

AF:

0.000543

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00453

AC:

5036

AN:

1112000

Other (OTH)

AF:

0.00508

AC:

307

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

327

654

981

1308

1635

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<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:

0.00286

AC:

435

AN:

152182

Hom.:

Cov.:

AF XY:

0.00263

AC XY:

196

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41522

American (AMR)

AF:

0.00321

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00229

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.000755

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00469

AC:

319

AN:

68010

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00454

Hom.:

Bravo

AF:

0.00317

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00305

AC:

370

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00486

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (10)

Fanconi anemia complementation group C (5)

not provided (5)

Fanconi anemia (3)

Hereditary cancer-predisposing syndrome (2)

Fanconi anemia complementation group A (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Benign

0.38

PROVEAN

Pathogenic

-5.6

REVEL

Uncertain

0.42

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.83

MVP

0.87

MPC

0.40

ClinPred

0.028

GERP RS

4.8

Varity_R

0.45

gMVP

0.49

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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