11-65859230-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

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: Splicing: ADA: 0.0002258
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.230
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000525451.6. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL1	ENST00000534769.5	TSL:2	c.117+2027G>A		intron	N/A	ENSP00000431696.1	E9PK25
	MUS81	ENST00000529857.5	TSL:5	c.9-995C>T		intron	N/A	ENSP00000431979.1	E9PII7
	CFL1	ENST00000525451.6	TSL:2	c.-532+1G>A		splice_donor intron	N/A	ENSP00000432660.1	P23528

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.167 AC: 1 AN: 6

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.200 AC: 6 AN: 30

Other (OTH) AF: 0.500 AC: 1 AN: 2

GnomAD4 genome AF: 0.298 AC: 45276 AN: 152032 Hom.: 7605 Cov.: 32 AF XY: 0.302 AC XY: 22464 AN XY: 74312

African (AFR) AF: 0.192 AC: 7984 AN: 41494

American (AMR) AF: 0.443 AC: 6773 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1216 AN: 3470

East Asian (EAS) AF: 0.655 AC: 3387 AN: 5172

South Asian (SAS) AF: 0.375 AC: 1810 AN: 4826

European-Finnish (FIN) AF: 0.282 AC: 2981 AN: 10558

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.295 AC: 20037 AN: 67926

Other (OTH) AF: 0.305 AC: 644 AN: 2110

Alfa AF: 0.303 Hom.: 11708

Bravo AF: 0.310

Asia WGS AF: 0.458 AC: 1588 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.090
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		-0.23
PromoterAI		-0.070	Neutral
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1939212; hg19: chr11-65626701;