19-38647712-C-T

Variant names:

• chr19-38647712-C-T
• rs1401036286
• NM_004924.6:c.-34C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_004924.6(ACTN4):​c.-34C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000394 in 1,521,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: ACTN4 NM_004924.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.222
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000198 (3/151768) while in subpopulation EAS AF = 0.000583 (3/5144). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	NM_004924.6	MANE Select	c.-34C>T		5_prime_UTR	Exon 1 of 21	NP_004915.2
	ACTN4	NM_001440296.1		c.-34C>T		5_prime_UTR	Exon 1 of 22	NP_001427225.1
	ACTN4	NM_001440300.1		c.-34C>T		5_prime_UTR	Exon 1 of 22	NP_001427229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACTN4	ENST00000252699.7	TSL:1 MANE Select	c.-34C>T		5_prime_UTR	Exon 1 of 21	ENSP00000252699.2	O43707-1
	ACTN4	ENST00000424234.7	TSL:1	c.-34C>T		5_prime_UTR	Exon 1 of 21	ENSP00000411187.4	F5GXS2
	ACTN4	ENST00000588618.5	TSL:1	n.64C>T		non_coding_transcript_exon	Exon 1 of 12

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151656 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 2 AN: 120736 AF XY: 0.0000304

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000458

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000219 AC: 3 AN: 1370078 Hom.: 0 Cov.: 31 AF XY: 0.00000296 AC XY: 2 AN XY: 675808

African (AFR) AF: 0.00 AC: 0 AN: 27984

American (AMR) AF: 0.0000299 AC: 1 AN: 33456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24006

East Asian (EAS) AF: 0.0000633 AC: 2 AN: 31590

South Asian (SAS) AF: 0.00 AC: 0 AN: 76556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067798

Other (OTH) AF: 0.00 AC: 0 AN: 56712

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151768 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74188

African (AFR) AF: 0.00 AC: 0 AN: 41478

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67770

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Focal segmental glomerulosclerosis 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.89
PhyloP100		0.22
PromoterAI		-0.036	Neutral
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.4
Mutation Taster		=105/195	disease causing

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: rs1401036286; hg19: chr19-39138352;