rs4621

Variant names:

• chr11-65856048-G-A
• rs4621
• NM_005507.3:c.198C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005507.3(CFL1):​c.198C>T​(p.Asp66Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.627 in 1,613,854 control chromosomes in the GnomAD database, including 328,492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23663 hom., cov: 31)
  • Exomes 𝑓: 0.64 (304829 hom.)
• Consequence: CFL1 NM_005507.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.96
• Publications: 35 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]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 11-65856048-G-A is Benign according to our data. Variant chr11-65856048-G-A is described in ClinVar as Benign. ClinVar VariationId is 1291237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.666 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFL1	NM_005507.3	c.198C>T	p.Asp66Asp	synonymous_variant	Exon 2 of 4	ENST00000308162.10	NP_005498.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFL1	ENST00000308162.10	c.198C>T	p.Asp66Asp	synonymous_variant	Exon 2 of 4	1	NM_005507.3	ENSP00000309629.5

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79828 AN: 151892 Hom.: 23668 Cov.: 31

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.587

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.706

Gnomad MID AF: 0.704

Gnomad NFE AF: 0.671

Gnomad OTH AF: 0.558

GnomAD2 exomes AF: 0.574 AC: 144299 AN: 251482 AF XY: 0.596

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.636

Gnomad EAS exome AF: 0.320

Gnomad FIN exome AF: 0.702

Gnomad NFE exome AF: 0.674

Gnomad OTH exome AF: 0.618

GnomAD4 exome AF: 0.638 AC: 932502 AN: 1461844 Hom.: 304829 Cov.: 62 AF XY: 0.641 AC XY: 466053 AN XY: 727232

African (AFR) AF: 0.249 AC: 8320 AN: 33480

American (AMR) AF: 0.378 AC: 16920 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 16620 AN: 26134

East Asian (EAS) AF: 0.323 AC: 12831 AN: 39698

South Asian (SAS) AF: 0.636 AC: 54836 AN: 86258

European-Finnish (FIN) AF: 0.700 AC: 37416 AN: 53420

Middle Eastern (MID) AF: 0.702 AC: 4048 AN: 5766

European-Non Finnish (NFE) AF: 0.669 AC: 744177 AN: 1111972

Other (OTH) AF: 0.618 AC: 37334 AN: 60394

GnomAD4 genome AF: 0.525 AC: 79835 AN: 152010 Hom.: 23663 Cov.: 31 AF XY: 0.528 AC XY: 39251 AN XY: 74306

African (AFR) AF: 0.262 AC: 10848 AN: 41442

American (AMR) AF: 0.469 AC: 7170 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.639 AC: 2215 AN: 3468

East Asian (EAS) AF: 0.318 AC: 1641 AN: 5164

South Asian (SAS) AF: 0.620 AC: 2982 AN: 4806

European-Finnish (FIN) AF: 0.706 AC: 7459 AN: 10570

Middle Eastern (MID) AF: 0.685 AC: 200 AN: 292

European-Non Finnish (NFE) AF: 0.671 AC: 45607 AN: 67976

Other (OTH) AF: 0.559 AC: 1179 AN: 2110

Alfa AF: 0.606 Hom.: 12942

Bravo AF: 0.491

Asia WGS AF: 0.489 AC: 1703 AN: 3478

EpiCase AF: 0.680

EpiControl AF: 0.689

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	6.9
DANN	Benign	0.93
PhyloP100		2.0
PromoterAI		0.0091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4621; hg19: chr11-65623519; COSMIC: COSV57378678; COSMIC: COSV57378678;