19-38700743-G-T

Variant names:

• chr19-38700743-G-T
• rs2112649
• NM_004924.6:c.277+29G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004924.6(ACTN4):​c.277+29G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,436,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00200
• Publications: 11 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004924.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.277+29G>T		intron	N/A	NP_004915.2
	ACTN4	NM_001440296.1		c.277+29G>T		intron	N/A	NP_001427225.1
	ACTN4	NM_001440300.1		c.277+29G>T		intron	N/A	NP_001427229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.277+29G>T		intron	N/A	ENSP00000252699.2
	ACTN4	ENST00000424234.7	TSL:1	c.277+29G>T		intron	N/A	ENSP00000411187.4
	ACTN4	ENST00000390009.7	TSL:1	c.163-13726G>T		intron	N/A	ENSP00000439497.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000111 AC: 16 AN: 1436854 Hom.: 0 Cov.: 28 AF XY: 0.00000977 AC XY: 7 AN XY: 716158

African (AFR) AF: 0.00 AC: 0 AN: 32918

American (AMR) AF: 0.00 AC: 0 AN: 44450

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39520

South Asian (SAS) AF: 0.00 AC: 0 AN: 85706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52140

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.0000147 AC: 16 AN: 1090922

Other (OTH) AF: 0.00 AC: 0 AN: 59622

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.6
DANN	Benign	0.62
PhyloP100		0.0020
RBP_binding_hub_radar		0.85
RBP_regulation_power_radar		2.1

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

Other links and lift over

dbSNP: rs2112649; hg19: chr19-39191383;