rs667555

chr11-65857091-A-Cchr11-65857091-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005507.3(CFL1):c.4-849T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 156,298 control chromosomes in the GnomAD database, including 26,283 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (25523 hom., cov: 33)
  • Exomes 𝑓: 0.59 (760 hom.)
• Consequence: CFL1 NM_005507.3 intron
• Scores: Splicing: ADA: 0.0001012
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.237

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.696 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFL1	NM_005507.3	c.4-849T>G		intron_variant		ENST00000308162.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFL1	ENST00000308162.10	c.4-849T>G		intron_variant		1	NM_005507.3	P1

Frequencies

GnomAD3 genomes AF: 0.546 AC: 82985 AN: 151982 Hom.: 25528 Cov.: 33

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.588

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.647

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.716

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.701

Gnomad OTH AF: 0.578

GnomAD4 exome AF: 0.595 AC: 2496 AN: 4198 Hom.: 760 Cov.: 0 AF XY: 0.599 AC XY: 1816 AN XY: 3034

Gnomad4 AFR exome AF: 0.300

Gnomad4 AMR exome AF: 0.304

Gnomad4 ASJ exome AF: 0.667

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.597

Gnomad4 FIN exome AF: 0.623

Gnomad4 NFE exome AF: 0.607

Gnomad4 OTH exome AF: 0.528

GnomAD4 genome AF: 0.546 AC: 82997 AN: 152100 Hom.: 25523 Cov.: 33 AF XY: 0.548 AC XY: 40702 AN XY: 74340

Gnomad4 AFR AF: 0.275

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.647

Gnomad4 EAS AF: 0.318

Gnomad4 SAS AF: 0.621

Gnomad4 FIN AF: 0.716

Gnomad4 NFE AF: 0.701

Gnomad4 OTH AF: 0.579

Alfa AF: 0.627 Hom.: 5826

Bravo AF: 0.512

Asia WGS AF: 0.492 AC: 1712 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	13
Dann	Benign	0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0040
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

LitVar

Other links and lift over

dbSNP: rs667555; hg19: chr11-65624562;