19-38647968-T-G

Variant names:

• chr19-38647968-T-G
• rs2303040
• NM_004924.6:c.162+61T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_004924.6(ACTN4):​c.162+61T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000764 in 1,171,004 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: 𝑓 0.0010 (0 hom., cov: 24)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: ACTN4 NM_004924.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00104 (132/126916) while in subpopulation AFR AF= 0.00245 (71/28982). AF 95% confidence interval is 0.00199. There are 0 homozygotes in gnomad4. There are 65 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTN4	NM_004924.6	c.162+61T>G		intron_variant	Intron 1 of 20	ENST00000252699.7	NP_004915.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTN4	ENST00000252699.7	c.162+61T>G		intron_variant	Intron 1 of 20	1	NM_004924.6	ENSP00000252699.2

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 132 AN: 126862 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000700

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000892

Gnomad MID AF: 0.00385

Gnomad NFE AF: 0.000418

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000731 AC: 763 AN: 1044088 Hom.: 0 Cov.: 21 AF XY: 0.000726 AC XY: 369 AN XY: 508294

Gnomad4 AFR exome AF: 0.00316

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00233

Gnomad4 SAS exome AF: 0.000445

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.000542

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00104 AC: 132 AN: 126916 Hom.: 0 Cov.: 24 AF XY: 0.00105 AC XY: 65 AN XY: 61728

Gnomad4 AFR AF: 0.00245

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000700

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000892

Gnomad4 NFE AF: 0.000418

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.65
DANN	Benign	0.46

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: rs2303040; hg19: chr19-39138608;