dbSNP rs587777741: ANLN:p.Arg431Ser (chr7-36411062-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_018685.5(ANLN):c.1291C>A(p.Arg431Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R431C) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ANLN
NM_018685.5 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANLN	NM_018685.5 link	c.1291C>A	p.Arg431Ser	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>A	p.Arg431Ser	missense_variant	Exon 7 of 24	1	NM_018685.5	ENSP00000265748.2		Q9NQW6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451626

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722142

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

32712

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

41330

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25770

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

39556

Gnomad4 SAS exome

AF:

0.0000119

AC:

AN:

83780

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

53318

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1109534

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

59916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.058

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.43

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.42

T;T

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.24

Gain of ubiquitination at K433 (P = 0.0292);Gain of ubiquitination at K433 (P = 0.0292);

MVP

0.80

MPC

0.62

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.69

Mutation Taster

=48/52

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.48

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.48

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over