11-65859230-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4BA1

The ENST00000525451.6(CFL1):​c.-532+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.298 in 152,072 control chromosomes in the GnomAD database, including 7,605 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 7605 hom., cov: 32)
Exomes 𝑓: 0.20 ( 0 hom. )

Consequence

CFL1
ENST00000525451.6 splice_donor, intron

Scores

2
Splicing: ADA: 0.0002258
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.230
Variant links:
Genes affected
CFL1 (HGNC:1874): (cofilin 1) The protein encoded by this gene can polymerize and depolymerize F-actin and G-actin in a pH-dependent manner. Increased phosphorylation of this protein by LIM kinase aids in Rho-induced reorganization of the actin cytoskeleton. Cofilin is a widely distributed intracellular actin-modulating protein that binds and depolymerizes filamentous F-actin and inhibits the polymerization of monomeric G-actin in a pH-dependent manner. It is involved in the translocation of actin-cofilin complex from cytoplasm to nucleus.[supplied by OMIM, Apr 2004]
MUS81 (HGNC:29814): (MUS81 structure-specific endonuclease subunit) This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.09).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.636 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFL1ENST00000534769.5 linkc.117+2027G>A intron_variant Intron 1 of 3 2 ENSP00000431696.1 E9PK25
MUS81ENST00000529857.5 linkc.9-995C>T intron_variant Intron 1 of 5 5 ENSP00000431979.1 E9PII7
CFL1ENST00000525451.6 linkc.-532+1G>A splice_donor_variant, intron_variant Intron 1 of 4 2 ENSP00000432660.1 P23528

Frequencies

GnomAD3 genomes
AF:
0.298
AC:
45234
AN:
151914
Hom.:
7592
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.192
Gnomad AMI
AF:
0.405
Gnomad AMR
AF:
0.444
Gnomad ASJ
AF:
0.350
Gnomad EAS
AF:
0.654
Gnomad SAS
AF:
0.375
Gnomad FIN
AF:
0.282
Gnomad MID
AF:
0.244
Gnomad NFE
AF:
0.295
Gnomad OTH
AF:
0.304
GnomAD4 exome
AF:
0.200
AC:
8
AN:
40
Hom.:
0
Cov.:
0
AF XY:
0.235
AC XY:
8
AN XY:
34
show subpopulations
Gnomad4 SAS exome
AF:
0.167
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.200
Gnomad4 OTH exome
AF:
0.500
GnomAD4 genome
AF:
0.298
AC:
45276
AN:
152032
Hom.:
7605
Cov.:
32
AF XY:
0.302
AC XY:
22464
AN XY:
74312
show subpopulations
Gnomad4 AFR
AF:
0.192
Gnomad4 AMR
AF:
0.443
Gnomad4 ASJ
AF:
0.350
Gnomad4 EAS
AF:
0.655
Gnomad4 SAS
AF:
0.375
Gnomad4 FIN
AF:
0.282
Gnomad4 NFE
AF:
0.295
Gnomad4 OTH
AF:
0.305
Alfa
AF:
0.304
Hom.:
8207
Bravo
AF:
0.310
Asia WGS
AF:
0.458
AC:
1588
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.090
CADD
Benign
13
DANN
Benign
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00023
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.63
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.63
Position offset: 1

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: rs1939212; hg19: chr11-65626701; API