rs145474119

Variant names:

• chr19-38724553-G-A
• rs145474119
• NM_004924.6:c.1998G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_004924.6(ACTN4):​c.1998G>A​(p.Gln666Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.00944 in 1,613,652 control chromosomes in the GnomAD database, including 118 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (110 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.91

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]

LOC107985291 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-38724553-G-A is Benign according to our data. Variant chr19-38724553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00658 (1002/152378) while in subpopulation NFE AF= 0.0111 (756/68044). AF 95% confidence interval is 0.0105. There are 8 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1002 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.1998G>A	p.Gln666Gln	synonymous_variant	Exon 16 of 21	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.1998G>A	p.Gln666Gln	synonymous_variant	Exon 16 of 21	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1004 AN: 152260 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00842 AC: 2106 AN: 250048 Hom.: 28 AF XY: 0.00872 AC XY: 1182 AN XY: 135510

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00882

Gnomad FIN exome AF: 0.00795

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00974 AC: 14234 AN: 1461274 Hom.: 110 Cov.: 36 AF XY: 0.00971 AC XY: 7057 AN XY: 726952

Gnomad4 AFR exome AF: 0.00173

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00879

Gnomad4 FIN exome AF: 0.00847

Gnomad4 NFE exome AF: 0.0112

Gnomad4 OTH exome AF: 0.00686

GnomAD4 genome AF: 0.00658 AC: 1002 AN: 152378 Hom.: 8 Cov.: 32 AF XY: 0.00627 AC XY: 467 AN XY: 74514

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00870

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00901 Hom.: 2

Bravo AF: 0.00584

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis Benign:1

Dec 15, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 1 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	8.7
DANN	Benign	0.74

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

Other links and lift over

dbSNP: rs145474119; hg19: chr19-39215193;