rs144388375

chr19-38721671-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004924.6(ACTN4):c.1425C>T(p.Ala475=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00305 in 1,613,662 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (16 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.922

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 19-38721671-C-T is Benign according to our data. Variant chr19-38721671-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38721671-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.922 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00211 (322/152366) while in subpopulation NFE AF= 0.00322 (219/68040). AF 95% confidence interval is 0.00287. There are 0 homozygotes in gnomad4. There are 157 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 322 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.1425C>T	p.Ala475=	synonymous_variant	12/21	ENST00000252699.7
LOC107985291	XR_001753937.2	n.169+6517G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.1425C>T	p.Ala475=	synonymous_variant	12/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.00211 AC: 322 AN: 152248 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00207 AC: 518 AN: 250578 Hom.: 3 AF XY: 0.00204 AC XY: 277 AN XY: 135590

Gnomad AFR exome AF: 0.000802

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00526

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00315 AC: 4599 AN: 1461296 Hom.: 16 Cov.: 32 AF XY: 0.00302 AC XY: 2194 AN XY: 727000

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00573

Gnomad4 NFE exome AF: 0.00371

Gnomad4 OTH exome AF: 0.00207

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152366 Hom.: 0 Cov.: 33 AF XY: 0.00211 AC XY: 157 AN XY: 74510

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00288 Hom.: 1

Bravo AF: 0.00187

EpiCase AF: 0.00316

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	ACTN4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2018	- -

Focal segmental glomerulosclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.12
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs144388375; hg19: chr19-39212311; COSMIC: COSV99399651; COSMIC: COSV99399651;