11-65857091-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005507.3(CFL1):​c.4-849T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFL1 NM_005507.3 intron
• Scores: Splicing: ADA: 0.00002463
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005507.3. 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
	CFL1	NM_005507.3	MANE Select	c.4-849T>A		intron	N/A	NP_005498.1	P23528

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFL1	ENST00000308162.10	TSL:1 MANE Select	c.4-849T>A		intron	N/A	ENSP00000309629.5	P23528
	CFL1	ENST00000534769.5	TSL:2	c.118-849T>A		intron	N/A	ENSP00000431696.1	E9PK25
	CFL1	ENST00000525451.6	TSL:2	c.4-849T>A		intron	N/A	ENSP00000432660.1	P23528

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4220 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3048

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.00 AC: 0 AN: 46

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12

East Asian (EAS) AF: 0.00 AC: 0 AN: 8

South Asian (SAS) AF: 0.00 AC: 0 AN: 2624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1242

Other (OTH) AF: 0.00 AC: 0 AN: 108

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 12829

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		-0.24
PromoterAI		0.0067	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
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;