11-65859230-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

The ENST00000525451.6(CFL1):c.-532+1G>A variant causes a splice donor 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
• Scores: Splicing: ADA: 0.0002258
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230

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]

ACMG classification

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/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFL1	ENST00000525451.6	c.-532+1G>A		splice_donor_variant		2		P1
CFL1	ENST00000526975.1	c.-244+1G>A		splice_donor_variant		3
CFL1	ENST00000531413.5	c.-49+1G>A		splice_donor_variant		3

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45234 AN: 151914 Hom.: 7592 Cov.: 32

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

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

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

Other links and lift over

dbSNP: rs1939212; hg19: chr11-65626701;