rs587777741

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS2_Supporting

The NM_018685.5(ANLN):c.1291C>T(p.Arg431Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000393 in 1,603,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

ANLN
NM_018685.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.90

Variant links:

Genes affected

ANLN (HGNC:14082): (anillin, actin binding protein) This gene encodes an actin-binding protein that plays a role in cell growth and migration, and in cytokinesis. The encoded protein is thought to regulate actin cytoskeletal dynamics in podocytes, components of the glomerulus. Mutations in this gene are associated with focal segmental glomerulosclerosis 8. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2014]

ANLN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.841

PP5

Variant 7-36411062-C-T is Pathogenic according to our data. Variant chr7-36411062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 156221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANLN	NM_018685.5 link	c.1291C>T	p.Arg431Cys	missense_variant	Exon 7 of 24	ENST00000265748.7	NP_061155.2	Q9NQW6-1A0A024RA49

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANLN	ENST00000265748.7 link	c.1291C>T	p.Arg431Cys	missense_variant	Exon 7 of 24	1	NM_018685.5	ENSP00000265748.2		Q9NQW6-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241526

Hom.:

AF XY:

0.0000153

AC XY:

AN XY:

130724

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000400

AC:

AN:

1451628

Hom.:

Cov.:

AF XY:

0.0000374

AC XY:

AN XY:

722142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000505

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000773

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Focal segmental glomerulosclerosis 8

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2014	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 26, 2022	ACMG codes: PS3, PP1_Strong, PP3 -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2024

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 431 of the ANLN protein (p.Arg431Cys). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with focal segmental glomerulosclerosis and/or steroid resistant nephrotic syndrome (PMID: 24676636, 30406062). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156221). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ANLN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ANLN function (PMID: 24676636). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.7

D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.028

D;D

Polyphen

0.99

D;D

Vest4

0.94

MVP

0.68

MPC

0.69

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.24

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over