rs7248577

Variant names:

• chr19-38718155-C-T
• rs7248577
• NM_004924.6:c.1291+81C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004924.6(ACTN4):​c.1291+81C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0653 in 1,550,290 control chromosomes in the GnomAD database, including 3,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (280 hom., cov: 32)
  • Exomes 𝑓: 0.066 (3352 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.572
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-38718155-C-T is Benign according to our data. Variant chr19-38718155-C-T is described in ClinVar as Benign. ClinVar VariationId is 1237308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0882 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.1291+81C>T		intron_variant	Intron 11 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.1291+81C>T		intron_variant	Intron 11 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.0598 AC: 9098 AN: 152132 Hom.: 280 Cov.: 32

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0622

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0461

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0633

Gnomad OTH AF: 0.0612

GnomAD4 exome AF: 0.0659 AC: 92165 AN: 1398040 Hom.: 3352 Cov.: 31 AF XY: 0.0669 AC XY: 46157 AN XY: 690050

African (AFR) AF: 0.0645 AC: 2045 AN: 31692

American (AMR) AF: 0.0733 AC: 2645 AN: 36066

Ashkenazi Jewish (ASJ) AF: 0.0620 AC: 1560 AN: 25176

East Asian (EAS) AF: 0.0465 AC: 1672 AN: 35950

South Asian (SAS) AF: 0.102 AC: 8081 AN: 79392

European-Finnish (FIN) AF: 0.0248 AC: 1199 AN: 48302

Middle Eastern (MID) AF: 0.0707 AC: 402 AN: 5688

European-Non Finnish (NFE) AF: 0.0656 AC: 70710 AN: 1077798

Other (OTH) AF: 0.0664 AC: 3851 AN: 57976

GnomAD4 genome AF: 0.0598 AC: 9107 AN: 152250 Hom.: 280 Cov.: 32 AF XY: 0.0588 AC XY: 4380 AN XY: 74442

African (AFR) AF: 0.0618 AC: 2568 AN: 41550

American (AMR) AF: 0.0620 AC: 949 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3470

East Asian (EAS) AF: 0.0462 AC: 239 AN: 5178

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4820

European-Finnish (FIN) AF: 0.0219 AC: 232 AN: 10612

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0633 AC: 4304 AN: 68006

Other (OTH) AF: 0.0620 AC: 131 AN: 2112

Alfa AF: 0.0562 Hom.: 30

Bravo AF: 0.0631

Asia WGS AF: 0.0900 AC: 312 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: 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	-0.79
CADD	Benign	1.3
DANN	Benign	0.83
PhyloP100		-0.57
Mutation Taster		=100/0	polymorphism (auto)

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: rs7248577; hg19: chr19-39208795;