chr9-95107185-C-T

Variant summary

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

The NM_000136.3(FANCC):​c.1414G>A​(p.Gly472Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,614,184 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G472E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

FANCC
NM_000136.3 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7O:1

Conservation

PhyloP100: 0.402

Publications

5 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]
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]

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=0.007597208).
BP6
Variant 9-95107185-C-T is Benign according to our data. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299. Variant chr9-95107185-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 134299.
BS2
High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCCNM_000136.3 linkc.1414G>A p.Gly472Arg missense_variant Exon 14 of 15 ENST00000289081.8 NP_000127.2 Q00597A0A024R9N2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCCENST00000289081.8 linkc.1414G>A p.Gly472Arg missense_variant Exon 14 of 15 1 NM_000136.3 ENSP00000289081.3 Q00597

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152202
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00166
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD2 exomes
AF:
0.000334
AC:
84
AN:
251292
AF XY:
0.000493
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000616
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000194
AC:
284
AN:
1461864
Hom.:
2
Cov.:
32
AF XY:
0.000296
AC XY:
215
AN XY:
727224
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33480
American (AMR)
AF:
0.0000447
AC:
2
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.0000765
AC:
2
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00262
AC:
226
AN:
86252
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53418
Middle Eastern (MID)
AF:
0.00104
AC:
6
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000342
AC:
38
AN:
1112000
Other (OTH)
AF:
0.000149
AC:
9
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.490
Heterozygous variant carriers
0
23
46
70
93
116
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.0000853
AC:
13
AN:
152320
Hom.:
0
Cov.:
33
AF XY:
0.000148
AC XY:
11
AN XY:
74470
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41576
American (AMR)
AF:
0.0000653
AC:
1
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.000576
AC:
2
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00166
AC:
8
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10614
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68028
Other (OTH)
AF:
0.000473
AC:
1
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.463
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000924
Hom.:
1
Bravo
AF:
0.0000529
ExAC
AF:
0.000404
AC:
49
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:7Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:3
Oct 13, 2020
GeneDx
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24728327, 21279724, 28767289) -

Mar 23, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Oct 01, 2020
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Fanconi anemia Uncertain:1Benign:1
Dec 10, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Aug 05, 2021
Sema4, Sema4
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Fanconi anemia complementation group C Uncertain:1Benign:1
Aug 19, 2020
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

May 18, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1Other:1
Oct 24, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: FANCC c.1414G>A (p.Gly472Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00033 in 251292 control chromosomes, predominantly at a frequency of 0.0025 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCC causing Fanconi Anemia Group C phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1414G>A has been reported in the literature in individuals affected with Pancreas cancer (example, Bhai_2021, Shindo_2017), without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C or other FANCC related diseases. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 28767289). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Likely benign, n=4, Benign, n=1, VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Hereditary cancer-predisposing syndrome Benign:1
Apr 03, 2023
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.58
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
12
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.40
.;T
M_CAP
Benign
0.0060
T
MetaRNN
Benign
0.0076
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
L;L
PhyloP100
0.40
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-2.0
N;N
REVEL
Benign
0.046
Sift
Benign
0.11
T;T
Sift4G
Benign
0.14
T;T
Polyphen
0.053
B;B
Vest4
0.13
MutPred
0.55
Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP
0.66
MPC
0.30
ClinPred
0.039
T
GERP RS
2.8
Varity_R
0.071
gMVP
0.094
Mutation Taster
=93/7
polymorphism

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

Other links and lift over

dbSNP: rs201063698; hg19: chr9-97869467; API