rs137985903

Variant names:

• chr19-38725729-C-T
• rs137985903
• NM_004924.6:c.2016C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004924.6(ACTN4):​c.2016C>T​(p.Ile672Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,613,732 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.96
• Publications: 0 publications found

Genes affected

ACTN4 (HGNC:166): (actinin alpha 4) Alpha actinins belong to the spectrin gene superfamily which represents a diverse group of cytoskeletal proteins, including the alpha and beta spectrins and dystrophins. Alpha actinin is an actin-binding protein with multiple roles in different cell types. In nonmuscle cells, the cytoskeletal isoform is found along microfilament bundles and adherens-type junctions, where it is involved in binding actin to the membrane. In contrast, skeletal, cardiac, and smooth muscle isoforms are localized to the Z-disc and analogous dense bodies, where they help anchor the myofibrillar actin filaments. This gene encodes a nonmuscle, alpha actinin isoform which is concentrated in the cytoplasm, and thought to be involved in metastatic processes. Mutations in this gene have been associated with focal and segmental glomerulosclerosis. [provided by RefSeq, Jul 2008]

ACTN4 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 1

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 19-38725729-C-T is Benign according to our data. Variant chr19-38725729-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 585360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.001 (153/152334) while in subpopulation AFR AF = 0.00349 (145/41572). AF 95% confidence interval is 0.00302. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 153 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.2016C>T	p.Ile672Ile	synonymous	Exon 17 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.2016C>T	p.Ile672Ile	synonymous	Exon 17 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.2016C>T	p.Ile672Ile	synonymous	Exon 17 of 22	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.2016C>T	p.Ile672Ile	synonymous	Exon 17 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.2016C>T	p.Ile672Ile	synonymous	Exon 17 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000390009.7	TSL:1	c.1359C>T	p.Ile453Ile	synonymous	Exon 10 of 14	ENSP00000439497.1	O43707-2

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000276 AC: 69 AN: 249812 AF XY: 0.000244

Gnomad AFR exome AF: 0.00316

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000887

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000129 AC: 188 AN: 1461398 Hom.: 0 Cov.: 32 AF XY: 0.000120 AC XY: 87 AN XY: 726966

African (AFR) AF: 0.00308 AC: 103 AN: 33470

American (AMR) AF: 0.000201 AC: 9 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53062

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111940

Other (OTH) AF: 0.000414 AC: 25 AN: 60376

GnomAD4 genome AF: 0.00100 AC: 153 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.000980 AC XY: 73 AN XY: 74502

African (AFR) AF: 0.00349 AC: 145 AN: 41572

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Focal segmental glomerulosclerosis 1 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.60
DANN	Benign	0.89
PhyloP100		-3.0
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.8
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137985903; hg19: chr19-39216369;