7-36396387-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_018685.5(ANLN):c.140C>G(p.Ala47Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000445 in 1,596,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ANLN
NM_018685.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 6.50

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09190199).

BP6

Variant 7-36396387-C-G is Benign according to our data. Variant chr7-36396387-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1437192.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

BS2

High AC in GnomAd at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANLN	NM_018685.5 linkuse as main transcript	c.140C>G	p.Ala47Gly	missense_variant	2/24	ENST00000265748.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANLN	ENST00000265748.7 linkuse as main transcript	c.140C>G	p.Ala47Gly	missense_variant	2/24	1	NM_018685.5	P2	Q9NQW6-1
ANLN	ENST00000396068.6 linkuse as main transcript	c.140C>G	p.Ala47Gly	missense_variant	2/23	1		A2	Q9NQW6-2
ANLN	ENST00000424865.1 linkuse as main transcript	c.74C>G	p.Ala25Gly	missense_variant	2/4	3
ANLN	ENST00000418118.1 linkuse as main transcript	c.74C>G	p.Ala25Gly	missense_variant	2/2	3

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249218

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134752

show subpopulations

Gnomad AFR exome

AF:

0.000619

Gnomad AMR exome

AF:

0.0000295

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000270

AC:

AN:

1444018

Hom.:

Cov.:

AF XY:

0.0000209

AC XY:

AN XY:

716690

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000505

GnomAD4 genome

AF:

0.000210

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000772

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000253

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 06, 2023

The c.140C>G (p.A47G) alteration is located in exon 2 (coding exon 2) of the ANLN gene. This alteration results from a C to G substitution at nucleotide position 140, causing the alanine (A) at amino acid position 47 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 26, 2022

ClinVar contains an entry for this variant (Variation ID: 1437192). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 47 of the ANLN protein (p.Ala47Gly). This variant is present in population databases (rs35765596, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ANLN-related conditions. -

ANLN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.39

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.;T;.

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.092

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.8

M;M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

N;N;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.010

D;D;D;D

Sift4G

Benign

0.067

T;D;D;D

Polyphen

0.99

D;D;.;.

Vest4

0.27

MVP

0.55

MPC

0.59

ClinPred

0.21

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.089

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

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