chr9-95172033-T-A

Variant names:

• chr9-95172033-T-A
• rs104886456
• NM_000136.3:c.456+4A>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PP3_Moderate PP5_Very_Strong

The NM_000136.3(FANCC):​c.456+4A>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000172 in 1,556,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000695432: The variant allele was found at a frequency of 0.00029 in 250510 control chromosomes. c.456+4A>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Group C (Yamashita_1996). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID:8639804)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: FANCC NM_000136.3 splice_region, intron
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 4.61
• Publications: 26 publications found

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: Labcorp Genetics (formerly Invitae), ClinGen, 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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000695432: The variant allele was found at a frequency of 0.00029 in 250510 control chromosomes. c.456+4A>T has been reported in the literature in multiple individuals affected with Fanconi Anemia Group C (Yamashita_1996). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 8639804).; SCV000916270: Patient-derived fibroblasts demonstrated that the c.456+4A>T variant significantly reduced DNA end-joining activity compared with wild type cells (Donahue et al. 2004).; SCV005044139: Functional studies demonstrated aberrant splicing and reduced DNA end-joining activity in patient-derived fibroblast cells carrying the c.456+4A>T variant [PMID: 8348157, 15364573].; SCV000149263: Published functional studies demonstrate a damaging effect: decreased nuclear localization, p53 phosphorylation and binding to co-factors in response to drug-induced DNA damage (Loke 2015); PMID: 31513304, 30792206, 26681312, 20301575, 28717661, 28495237, 27832981, 28425259, 28627524, 30683899, 30322717, 30676620, 20869034, 25236480, 7492758, 25545896, 30249500, 32570879, 30945166, 31558676, 25652403, 32235514, 8734810, 32885271, 34308366, 34426522; SCV004218679: Functional studies have demonstrated this variant leads to exon skipping (PMID: 8348157 (1993)) and decreased DNA end joining ability (PMID: 15364573 (2004)).; SCV006325159: "In vitro splice prediction programs and in vitro RNA splicing studies indicate that this sequence change results in altered splicing of the FANCC gene and produces an altered FANCC protein product with reduced function (PMIDs: 8348157, 15364573)."; SCV001142398: Whitney et al reported that this variant resulted exon skipping due to abnormal gene splicing (PMID: 8348157).; SCV000673287: RNA studies have demonstrated that this alteration results in aberrant mRNA splicing (Whitney MA et al. Nat. Genet. 1993 Jun;4:202-5; Chandrasekharappa SC et al. Blood. 2013 May;121:e138-4).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-95172033-T-A is Pathogenic according to our data. Variant chr9-95172033-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 12045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	NM_000136.3	MANE Select	c.456+4A>T		splice_region intron	N/A	NP_000127.2	Q00597
	FANCC	NM_001243743.2		c.456+4A>T		splice_region intron	N/A	NP_001230672.1	A0A024R9N2
	FANCC	NM_001243744.2		c.456+4A>T		splice_region intron	N/A	NP_001230673.1	A0A087WW44

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCC	ENST00000289081.8	TSL:1 MANE Select	c.456+4A>T		splice_region intron	N/A	ENSP00000289081.3	Q00597
	FANCC	ENST00000375305.6	TSL:1	c.456+4A>T		splice_region intron	N/A	ENSP00000364454.1	Q00597
	FANCC	ENST00000490972.7	TSL:1	c.456+4A>T		splice_region intron	N/A	ENSP00000479931.1	A0A087WW44

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000287 AC: 72 AN: 250510 AF XY: 0.000273

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00606

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000706

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000167 AC: 235 AN: 1404378 Hom.: 0 Cov.: 25 AF XY: 0.000175 AC XY: 123 AN XY: 702208

African (AFR) AF: 0.0000625 AC: 2 AN: 31996

American (AMR) AF: 0.0000224 AC: 1 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00676 AC: 174 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.00 AC: 0 AN: 85012

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.0000283 AC: 30 AN: 1060248

Other (OTH) AF: 0.000480 AC: 28 AN: 58370

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152230 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

Alfa AF: 0.000647 Hom.: 0

Bravo AF: 0.000204

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Fanconi anemia complementation group C (13)
5	-	-	not provided (5)
3	-	-	Fanconi anemia (3)
1	-	-	FANCC-related disorder (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.95
PhyloP100		4.6
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.48		Position offset: 44
DS_DL_spliceai		0.89		Position offset: 4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs104886456;

hg19: chr9-97934315;

COSMIC: COSV56656439;