ENST00000534769.5:c.117+2027G>A

Variant names:

• chr11-65859230-C-T
• rs1939212
• ENST00000534769.5:c.117+2027G>A

Variant summary

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

The ENST00000534769.5(CFL1):​c.117+2027G>A variant causes a 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. 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 ENST00000534769.5 intron
• 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 rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFL1	ENST00000534769.5	c.117+2027G>A		intron_variant	Intron 1 of 3	2		ENSP00000431696.1
MUS81	ENST00000529857.5	c.9-995C>T		intron_variant	Intron 1 of 5	5		ENSP00000431979.1
CFL1	ENST00000525451.6	c.-532+1G>A		splice_donor_variant, intron_variant	Intron 1 of 4	2		ENSP00000432660.1

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;