rs2368392

Positions:

• chr10-29545074-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021738.3(SVIL):​c.827+5523C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 533,674 control chromosomes in the GnomAD database, including 22,322 homozygotes. 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 0.30 (6759 hom., cov: 31)
  • Exomes 𝑓: 0.28 (15563 hom.)
• Consequence: SVIL NM_021738.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.391

Genes affected

SVIL (HGNC:11480): (supervillin) This gene encodes a bipartite protein with distinct amino- and carboxy-terminal domains. The amino-terminus contains nuclear localization signals and the carboxy-terminus contains numerous consecutive sequences with extensive similarity to proteins in the gelsolin family of actin-binding proteins, which cap, nucleate, and/or sever actin filaments. The gene product is tightly associated with both actin filaments and plasma membranes, suggesting a role as a high-affinity link between the actin cytoskeleton and the membrane. The encoded protein appears to aid in both myosin II assembly during cell spreading and disassembly of focal adhesions. Several transcript variants encoding different isoforms of supervillin have been described. [provided by RefSeq, Apr 2016]

MIR604 (HGNC:32860): (microRNA 604) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SVIL	NM_021738.3	c.827+5523C>T		intron_variant		ENST00000355867.9	NP_068506.2
MIR604	NR_030335.1	n.24C>T		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.827+5523C>T		intron_variant		1	NM_021738.3	ENSP00000348128	A2
MIR604	ENST00000384880.1	n.24C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44902 AN: 151698 Hom.: 6754 Cov.: 31

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.273

GnomAD3 exomes AF: 0.285 AC: 71343 AN: 250422 Hom.: 10425 AF XY: 0.281 AC XY: 38097 AN XY: 135580

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.340

Gnomad SAS exome AF: 0.318

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.280 AC: 107062 AN: 381858 Hom.: 15563 Cov.: 0 AF XY: 0.280 AC XY: 60900 AN XY: 217412

Gnomad4 AFR exome AF: 0.364

Gnomad4 AMR exome AF: 0.302

Gnomad4 ASJ exome AF: 0.166

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.262

Gnomad4 OTH exome AF: 0.273

GnomAD4 genome AF: 0.296 AC: 44926 AN: 151816 Hom.: 6759 Cov.: 31 AF XY: 0.298 AC XY: 22116 AN XY: 74218

Gnomad4 AFR AF: 0.359

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.161

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.302

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.271

Alfa AF: 0.270 Hom.: 3695

Bravo AF: 0.298

Asia WGS AF: 0.343 AC: 1190 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.6
DANN	Benign	0.58

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: rs2368392; hg19: chr10-29834003; COSMIC: COSV63441410;