rs12986337

Positions:

• chr19-38724532-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004924.6(ACTN4):​c.1977T>C​(p.Asn659=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,613,590 control chromosomes in the GnomAD database, including 3,757 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (265 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3492 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00600

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-38724532-T-C is Benign according to our data. Variant chr19-38724532-T-C is described in ClinVar as [Benign]. Clinvar id is 259571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38724532-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.006 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.1977T>C	p.Asn659=	synonymous_variant	16/21	ENST00000252699.7	NP_004915.2
LOC107985291	XR_001753937.2	n.169+3656A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.1977T>C	p.Asn659=	synonymous_variant	16/21	1	NM_004924.6	ENSP00000252699	A1

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8693 AN: 152084 Hom.: 266 Cov.: 32

Gnomad AFR AF: 0.0502

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0617

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.0460

Gnomad SAS AF: 0.0967

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0578

GnomAD3 exomes AF: 0.0635 AC: 15909 AN: 250450 Hom.: 590 AF XY: 0.0651 AC XY: 8829 AN XY: 135680

Gnomad AFR exome AF: 0.0509

Gnomad AMR exome AF: 0.0698

Gnomad ASJ exome AF: 0.0615

Gnomad EAS exome AF: 0.0405

Gnomad SAS exome AF: 0.105

Gnomad FIN exome AF: 0.0279

Gnomad NFE exome AF: 0.0628

Gnomad OTH exome AF: 0.0679

GnomAD4 exome AF: 0.0659 AC: 96234 AN: 1461388 Hom.: 3492 Cov.: 38 AF XY: 0.0668 AC XY: 48593 AN XY: 727006

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.0729

Gnomad4 ASJ exome AF: 0.0632

Gnomad4 EAS exome AF: 0.0457

Gnomad4 SAS exome AF: 0.102

Gnomad4 FIN exome AF: 0.0305

Gnomad4 NFE exome AF: 0.0657

Gnomad4 OTH exome AF: 0.0661

GnomAD4 genome AF: 0.0571 AC: 8697 AN: 152202 Hom.: 265 Cov.: 32 AF XY: 0.0563 AC XY: 4194 AN XY: 74430

Gnomad4 AFR AF: 0.0502

Gnomad4 AMR AF: 0.0615

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.0461

Gnomad4 SAS AF: 0.0961

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0638

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0595 Hom.: 115

Bravo AF: 0.0594

Asia WGS AF: 0.0890 AC: 311 AN: 3478

EpiCase AF: 0.0649

EpiControl AF: 0.0670

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Focal segmental glomerulosclerosis 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 12, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Dec 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.1
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12986337; hg19: chr19-39215172; COSMIC: COSV53142966; COSMIC: COSV53142966;