rs138139611

Positions:

• chr19-38728008-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.2400C>T​(p.Asp800=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,612,944 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00041 (1 hom.)
• Consequence: ACTN4 NM_004924.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.29

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=-0.36).
• BP6: Variant 19-38728008-C-T is Benign according to our data. Variant chr19-38728008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 585361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00067 (102/152138) while in subpopulation EAS AF= 0.00504 (26/5156). AF 95% confidence interval is 0.00353. There are 0 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 102 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACTN4	NM_004924.6	c.2400C>T	p.Asp800=	synonymous_variant	19/21	ENST00000252699.7
LOC107985291	XR_001753937.2	n.169+180G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACTN4	ENST00000252699.7	c.2400C>T	p.Asp800=	synonymous_variant	19/21	1	NM_004924.6	A1

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 103 AN: 152020 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00500

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00115 AC: 285 AN: 248420 Hom.: 1 AF XY: 0.00110 AC XY: 149 AN XY: 134920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00694

Gnomad SAS exome AF: 0.000820

Gnomad FIN exome AF: 0.00495

Gnomad NFE exome AF: 0.000188

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000411 AC: 600 AN: 1460806 Hom.: 1 Cov.: 32 AF XY: 0.000424 AC XY: 308 AN XY: 726676

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00358

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00506

Gnomad4 NFE exome AF: 0.0000917

Gnomad4 OTH exome AF: 0.000530

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152138 Hom.: 0 Cov.: 31 AF XY: 0.000834 AC XY: 62 AN XY: 74376

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00504

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00500

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000265 Hom.: 0

Bravo AF: 0.000302

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 30, 2023	- -

Focal segmental glomerulosclerosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

Focal segmental glomerulosclerosis 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	13
DANN	Benign	0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs138139611; hg19: chr19-39218648;