rs1157717956
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM4
The NM_000135.4(FANCA):c.3778_3783delCTTTTC(p.Leu1260_Phe1261del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000137 in 1,461,232 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
FANCA
NM_000135.4 conservative_inframe_deletion
NM_000135.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.09
Publications
0 publications found
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]
ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification was made for transcript
Our verdict: Likely_pathogenic. The variant received 6 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 27 uncertain in NM_000135.4
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000135.4.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000135.4. 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 |
|---|---|---|---|---|---|---|---|---|---|
| FANCA | NM_000135.4 | MANE Select | c.3778_3783delCTTTTC | p.Leu1260_Phe1261del | conservative_inframe_deletion | Exon 38 of 43 | NP_000126.2 | ||
| ZNF276 | NM_001113525.2 | MANE Select | c.*2608_*2613delGGAAAA | 3_prime_UTR | Exon 11 of 11 | NP_001106997.1 | |||
| FANCA | NM_001286167.3 | c.3778_3783delCTTTTC | p.Leu1260_Phe1261del | conservative_inframe_deletion | Exon 38 of 43 | NP_001273096.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| FANCA | ENST00000389301.8 | TSL:1 MANE Select | c.3778_3783delCTTTTC | p.Leu1260_Phe1261del | conservative_inframe_deletion | Exon 38 of 43 | ENSP00000373952.3 | ||
| ZNF276 | ENST00000443381.7 | TSL:1 MANE Select | c.*2608_*2613delGGAAAA | 3_prime_UTR | Exon 11 of 11 | ENSP00000415836.2 | |||
| ZNF276 | ENST00000289816.9 | TSL:1 | c.*2608_*2613delGGAAAA | 3_prime_UTR | Exon 11 of 11 | ENSP00000289816.5 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD2 exomes AF: 0.00000399 AC: 1AN: 250374 AF XY: 0.00 show subpopulations
GnomAD2 exomes
AF:
AC:
1
AN:
250374
AF XY:
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461232Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726844 show subpopulations ⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
GnomAD4 exome
AF:
AC:
2
AN:
1461232
Hom.:
AF XY:
AC XY:
0
AN XY:
726844
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
33454
American (AMR)
AF:
AC:
1
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26130
East Asian (EAS)
AF:
AC:
0
AN:
39690
South Asian (SAS)
AF:
AC:
0
AN:
86138
European-Finnish (FIN)
AF:
AC:
0
AN:
53360
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111632
Other (OTH)
AF:
AC:
0
AN:
60366
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
-
1
-
FANCA-related disorder (1)
-
1
-
Fanconi anemia (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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