NM_018685.5:c.554G>A

Variant names:

• chr7-36406247-G-A
• rs197367
• NM_018685.5:c.554G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018685.5(ANLN):​c.554G>A​(p.Arg185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.636 in 1,613,538 control chromosomes in the GnomAD database, including 328,974 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R185Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (27209 hom., cov: 33)
  • Exomes 𝑓: 0.64 (301765 hom.)
• Consequence: ANLN NM_018685.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.49
• Publications: 32 publications found

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 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 8

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.575349E-7).
• BP6: Variant 7-36406247-G-A is Benign according to our data. Variant chr7-36406247-G-A is described in ClinVar as Benign. ClinVar VariationId is 261051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.735 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018685.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANLN	NM_018685.5	MANE Select	c.554G>A	p.Arg185Lys	missense	Exon 4 of 24	NP_061155.2
	ANLN	NM_001284301.3		c.554G>A	p.Arg185Lys	missense	Exon 4 of 23	NP_001271230.1
	ANLN	NM_001284302.3		c.554G>A	p.Arg185Lys	missense	Exon 4 of 23	NP_001271231.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANLN	ENST00000265748.7	TSL:1 MANE Select	c.554G>A	p.Arg185Lys	missense	Exon 4 of 24	ENSP00000265748.2
	ANLN	ENST00000396068.6	TSL:1	c.554G>A	p.Arg185Lys	missense	Exon 4 of 23	ENSP00000379380.2
	ANLN	ENST00000424865.1	TSL:3	c.488G>A	p.Arg163Lys	missense	Exon 4 of 4	ENSP00000404979.1

Frequencies

GnomAD3 genomes AF: 0.590 AC: 89711 AN: 151924 Hom.: 27182 Cov.: 33

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.811

Gnomad AMR AF: 0.595

Gnomad ASJ AF: 0.697

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.756

Gnomad FIN AF: 0.689

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.631

Gnomad OTH AF: 0.589

GnomAD2 exomes AF: 0.654 AC: 164409 AN: 251334 AF XY: 0.660

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.669

Gnomad ASJ exome AF: 0.691

Gnomad EAS exome AF: 0.727

Gnomad FIN exome AF: 0.691

Gnomad NFE exome AF: 0.632

Gnomad OTH exome AF: 0.648

GnomAD4 exome AF: 0.641 AC: 936326 AN: 1461496 Hom.: 301765 Cov.: 52 AF XY: 0.644 AC XY: 468078 AN XY: 726984

African (AFR) AF: 0.439 AC: 14690 AN: 33474

American (AMR) AF: 0.659 AC: 29462 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 18184 AN: 26132

East Asian (EAS) AF: 0.746 AC: 29592 AN: 39692

South Asian (SAS) AF: 0.743 AC: 64115 AN: 86238

European-Finnish (FIN) AF: 0.684 AC: 36527 AN: 53410

Middle Eastern (MID) AF: 0.600 AC: 3462 AN: 5768

European-Non Finnish (NFE) AF: 0.631 AC: 701687 AN: 1111680

Other (OTH) AF: 0.639 AC: 38607 AN: 60388

GnomAD4 genome AF: 0.591 AC: 89790 AN: 152042 Hom.: 27209 Cov.: 33 AF XY: 0.597 AC XY: 44384 AN XY: 74348

African (AFR) AF: 0.447 AC: 18546 AN: 41452

American (AMR) AF: 0.596 AC: 9094 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.697 AC: 2420 AN: 3472

East Asian (EAS) AF: 0.723 AC: 3741 AN: 5174

South Asian (SAS) AF: 0.755 AC: 3645 AN: 4826

European-Finnish (FIN) AF: 0.689 AC: 7303 AN: 10594

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.631 AC: 42877 AN: 67944

Other (OTH) AF: 0.591 AC: 1244 AN: 2106

Alfa AF: 0.620 Hom.: 58287

Bravo AF: 0.574

TwinsUK AF: 0.623 AC: 2310

ALSPAC AF: 0.628 AC: 2421

ESP6500AA AF: 0.433 AC: 1906

ESP6500EA AF: 0.594 AC: 5105

ExAC AF: 0.650 AC: 78914

Asia WGS AF: 0.725 AC: 2517 AN: 3478

EpiCase AF: 0.624

EpiControl AF: 0.619

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Focal segmental glomerulosclerosis 8 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.9
DANN	Benign	0.64
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.1	N
PhyloP100		1.5
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.081
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.028
MPC		0.13
ClinPred		0.0022	T
GERP RS		3.6
Varity_R		0.041
gMVP		0.12
Mutation Taster		=100/0	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: rs197367; hg19: chr7-36445856; COSMIC: COSV56076351; COSMIC: COSV56076351;