rs667555

Variant names:

• chr11-65857091-A-C
• rs667555
• NM_005507.3:c.4-849T>G

Your query was ambiguous. Multiple possible variants found:

• chr11-65857091-A-C
• chr11-65857091-A-T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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]

SNX32 (HGNC:26423): (sorting nexin 32) Predicted to enable phosphatidylinositol binding activity. Predicted to be involved in retrograde transport, endosome to Golgi. Predicted to be located in cytosol. Predicted to be active in endosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CFL1	NM_005507.3	c.4-849T>G		intron_variant	Intron 1 of 3	ENST00000308162.10	NP_005498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFL1	ENST00000308162.10	c.4-849T>G		intron_variant	Intron 1 of 3	1	NM_005507.3	ENSP00000309629.5

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

African (AFR) AF: 0.300 AC: 3 AN: 10

American (AMR) AF: 0.304 AC: 14 AN: 46

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 8 AN: 12

East Asian (EAS) AF: 0.125 AC: 1 AN: 8

South Asian (SAS) AF: 0.597 AC: 1559 AN: 2610

European-Finnish (FIN) AF: 0.623 AC: 101 AN: 162

Middle Eastern (MID) AF: 0.500 AC: 4 AN: 8

European-Non Finnish (NFE) AF: 0.607 AC: 750 AN: 1236

Other (OTH) AF: 0.528 AC: 56 AN: 106

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

African (AFR) AF: 0.275 AC: 11416 AN: 41494

American (AMR) AF: 0.490 AC: 7493 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.647 AC: 2246 AN: 3472

East Asian (EAS) AF: 0.318 AC: 1642 AN: 5168

South Asian (SAS) AF: 0.621 AC: 2995 AN: 4826

European-Finnish (FIN) AF: 0.716 AC: 7570 AN: 10574

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.701 AC: 47673 AN: 67964

Other (OTH) AF: 0.579 AC: 1223 AN: 2112

Alfa AF: 0.656 Hom.: 12829

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
PhyloP100		-0.24
PromoterAI		0.064	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs667555; hg19: chr11-65624562;