rs1380850249

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_000135.4(FANCA):​c.3605_3607delAAG​(p.Glu1202del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,459,550 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

FANCA
NM_000135.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 1.21
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000135.4. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 16-89744977-CCTT-C is Pathogenic according to our data. Variant chr16-89744977-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 526377.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=3}. Variant chr16-89744977-CCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
FANCANM_000135.4 linkuse as main transcriptc.3605_3607delAAG p.Glu1202del disruptive_inframe_deletion 36/43 ENST00000389301.8 NP_000126.2 O15360-1
FANCANM_001286167.3 linkuse as main transcriptc.3605_3607delAAG p.Glu1202del disruptive_inframe_deletion 36/43 NP_001273096.1 O15360-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
FANCAENST00000389301.8 linkuse as main transcriptc.3605_3607delAAG p.Glu1202del disruptive_inframe_deletion 36/431 NM_000135.4 ENSP00000373952.3 O15360-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1459550
Hom.:
0
AF XY:
0.0000138
AC XY:
10
AN XY:
726172
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000216
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:6Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseFeb 28, 2020Curator: Arleen D. Auerbach. Submitter to LOVD: Johan de Winter. -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJan 29, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingCounsylDec 18, 2017- -
Likely pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 09, 2024Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Fanconi anemia, complementation group A (MIM#227650). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0216 - In-frame insertion/deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable in-frame deletion variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two compound heterozygous individuals with Fanconi Anaemia (PMID: 17924555, 29098742). It has also been classified as pathogenic by diagnostic laboratories in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 27, 2024- -
Fanconi anemia Pathogenic:2
Likely pathogenic, no assertion criteria providedclinical testingNatera, Inc.Dec 21, 2020- -
Likely pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 04, 2023In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 526377). This variant is also known as c.3602_3604del. This variant has been observed in individual(s) with Fanconi anemia (PMID: 17924555, 29098742). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This variant, c.3605_3607del, results in the deletion of 1 amino acid(s) of the FANCA protein (p.Glu1202del), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1380850249; hg19: chr16-89811385; API