rs12416605

Positions:

• chr10-29602331-C-T

Variant summary

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

The NM_021738.3(SVIL):​c.-201+32089G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.226 in 528,900 control chromosomes in the GnomAD database, including 15,710 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 0.20 (3892 hom., cov: 32)
  • Exomes 𝑓: 0.24 (11818 hom.)
• Consequence: SVIL NM_021738.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30

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]

MIR938 (HGNC:33681): (microRNA 938) 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=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SVIL	NM_021738.3	c.-201+32089G>A		intron_variant		ENST00000355867.9	NP_068506.2
MIR938	NR_030634.1	n.16G>A		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.-201+32089G>A		intron_variant		1	NM_021738.3	ENSP00000348128	A2
MIR938	ENST00000401216.1	n.16G>A		mature_miRNA_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30204 AN: 151870 Hom.: 3891 Cov.: 32

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.220

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.196

GnomAD3 exomes AF: 0.222 AC: 54766 AN: 246202 Hom.: 7075 AF XY: 0.221 AC XY: 29542 AN XY: 133452

Gnomad AFR exome AF: 0.0542

Gnomad AMR exome AF: 0.247

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.0325

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.263

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.237 AC: 89278 AN: 376912 Hom.: 11818 Cov.: 0 AF XY: 0.231 AC XY: 49471 AN XY: 214512

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.250

Gnomad4 ASJ exome AF: 0.215

Gnomad4 EAS exome AF: 0.0326

Gnomad4 SAS exome AF: 0.162

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.231

GnomAD4 genome AF: 0.199 AC: 30208 AN: 151988 Hom.: 3892 Cov.: 32 AF XY: 0.201 AC XY: 14937 AN XY: 74294

Gnomad4 AFR AF: 0.0588

Gnomad4 AMR AF: 0.215

Gnomad4 ASJ AF: 0.220

Gnomad4 EAS AF: 0.0380

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.198

Alfa AF: 0.253 Hom.: 5622

Bravo AF: 0.182

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.73

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: rs12416605; hg19: chr10-29891260; COSMIC: COSV63442821;