chr16-89799172-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000135.4(FANCA):​c.887G>A​(p.Arg296Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R296T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

FANCA
NM_000135.4 missense

Scores

19

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.197

Publications

0 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: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
  • Fanconi anemia
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.05869457).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
FANCANM_000135.4 linkc.887G>A p.Arg296Lys missense_variant Exon 10 of 43 ENST00000389301.8 NP_000126.2 O15360-1
FANCANM_001286167.3 linkc.887G>A p.Arg296Lys missense_variant Exon 10 of 43 NP_001273096.1 O15360-3
FANCANM_001018112.3 linkc.887G>A p.Arg296Lys missense_variant Exon 10 of 11 NP_001018122.1 O15360-2
FANCANM_001351830.2 linkc.791G>A p.Arg264Lys missense_variant Exon 9 of 10 NP_001338759.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCAENST00000389301.8 linkc.887G>A p.Arg296Lys missense_variant Exon 10 of 43 1 NM_000135.4 ENSP00000373952.3 O15360-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
8.3
DANN
Benign
0.49
DEOGEN2
Benign
0.055
T;.;.;T;T;.
Eigen
Benign
-1.5
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.043
N
LIST_S2
Benign
0.48
T;T;T;T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.059
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.99
L;L;L;.;.;.
PhyloP100
-0.20
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.23
N;N;N;N;N;N
REVEL
Benign
0.016
Sift
Benign
0.45
T;T;T;T;T;T
Sift4G
Benign
0.95
T;T;T;T;T;T
Polyphen
0.0010
B;.;B;.;B;B
Vest4
0.063
MutPred
0.41
Gain of methylation at R296 (P = 0.0016);Gain of methylation at R296 (P = 0.0016);Gain of methylation at R296 (P = 0.0016);Gain of methylation at R296 (P = 0.0016);Gain of methylation at R296 (P = 0.0016);.;
MVP
0.56
ClinPred
0.019
T
GERP RS
-0.44
Varity_R
0.079
gMVP
0.19
Mutation Taster
=88/12
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: rs878853667; hg19: chr16-89865580; API