chr19-38723996-G-A

Variant names:

• chr19-38723996-G-A
• rs150183570
• NM_004924.6:c.1611G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001440296.1(ACTN4):​c.1611G>A​(p.Ala537Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,680 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0046 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (3 hom.)
• Consequence: ACTN4 NM_001440296.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -6.80
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298338 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 19-38723996-G-A is Benign according to our data. Variant chr19-38723996-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259568.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-6.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00464 (706/152082) while in subpopulation AFR AF = 0.0154 (638/41466). AF 95% confidence interval is 0.0144. There are 6 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 706 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001440296.1. 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
	ACTN4	NM_004924.6	MANE Select	c.1611G>A	p.Ala537Ala	synonymous	Exon 14 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.1611G>A	p.Ala537Ala	synonymous	Exon 14 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.1611G>A	p.Ala537Ala	synonymous	Exon 14 of 22	NP_001427229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.1611G>A	p.Ala537Ala	synonymous	Exon 14 of 21	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.1611G>A	p.Ala537Ala	synonymous	Exon 14 of 21	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.954G>A	p.Ala318Ala	synonymous	Exon 7 of 14	ENSP00000439497.1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 707 AN: 151964 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00156 AC: 391 AN: 251244 AF XY: 0.00122

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000661 AC: 966 AN: 1461598 Hom.: 3 Cov.: 37 AF XY: 0.000622 AC XY: 452 AN XY: 727104

African (AFR) AF: 0.0141 AC: 473 AN: 33480

American (AMR) AF: 0.00257 AC: 115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53142

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.000241 AC: 268 AN: 1111998

Other (OTH) AF: 0.00147 AC: 89 AN: 60394

GnomAD4 genome AF: 0.00464 AC: 706 AN: 152082 Hom.: 6 Cov.: 32 AF XY: 0.00468 AC XY: 348 AN XY: 74306

African (AFR) AF: 0.0154 AC: 638 AN: 41466

American (AMR) AF: 0.00236 AC: 36 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 67978

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00256 Hom.: 2

Bravo AF: 0.00552

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Focal segmental glomerulosclerosis 1 (2)
-	-	1	Focal segmental glomerulosclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.13
DANN	Benign	0.77
PhyloP100		-6.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs150183570; hg19: chr19-39214636; COSMIC: COSV107260333; COSMIC: COSV107260333;