chr9-95249289-C-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000136.3(FANCC):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,770 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FANCC
NM_000136.3 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 5.31

Publications

2 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 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group C
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
colorectal cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
malignant pancreatic neoplasm
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
ovarian cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

FANCC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 14 pathogenic variants. Next in-frame start position is after 16 codons. Genomic position: 95249246. Lost 0.027 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-95249289-C-A is Pathogenic according to our data. Variant chr9-95249289-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 557034.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCC	NM_000136.3 link	c.3G>T	p.Met1?	start_lost	Exon 2 of 15	ENST00000289081.8	NP_000127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCC	ENST00000289081.8 link	c.3G>T	p.Met1?	start_lost	Exon 2 of 15	1	NM_000136.3	ENSP00000289081.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

250170

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53352

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111974

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Fanconi anemia complementation group C

Pathogenic:1

Mar 07, 2018

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome

Pathogenic:1

Sep 15, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the FANCC gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon (ATG). Although there is an alternate in-frame methionine 16 amino acids downstream from the initiation site, alterations truncating the protein between p.M1 and p.M16 are identified in many patients with Fanconi Anemia (Chandrasekharappa SC et al. Blood, 2013 May;121:e138-48; Steinberg-Shemer O et al. Haematologica, 2020 07;105:1825-1834; Murer-Orlando M et al. Lancet, 1993 Sep;342:686; Verlander PC et al. Am J Hum Genet, 1994 Apr;54:595-601; Gillio AP et al. Blood, 1997 Jul;90:105-10; Nicchia E et al. Mol Genet Genomic Med, 2015 Nov;3:500-12). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.21

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;D;T;.;T;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.71

LIST_S2

Benign

0.0

.;D;D;D;D;D;D;D

M_CAP

Benign

0.057

MetaRNN

Pathogenic

0.83

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.

PhyloP100

5.3

PROVEAN

Uncertain

-2.7

D;D;.;.;D;.;.;.

Sift

Pathogenic

0.0

D;D;.;.;D;.;.;.

Sift4G

Pathogenic

0.0

D;D;D;.;D;.;.;.

Vest4

0.91

ClinPred

0.99

GERP RS

5.1

PromoterAI

-0.058

Neutral

(source)

Varity_R

0.80

gMVP

0.38

Mutation Taster

=32/168

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over