rs12416605

Variant names:

• chr10-29602331-C-T
• rs12416605
• NM_021738.3:c.-201+32089G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 30 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SVIL	NM_021738.3	c.-201+32089G>A		intron_variant	Intron 1 of 37	ENST00000355867.9	NP_068506.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.-201+32089G>A		intron_variant	Intron 1 of 37	1	NM_021738.3	ENSP00000348128.4

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

GnomAD2 exomes AF: 0.222 AC: 54766 AN: 246202 AF XY: 0.221

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 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

African (AFR) AF: 0.0531 AC: 552 AN: 10402

American (AMR) AF: 0.250 AC: 8803 AN: 35278

Ashkenazi Jewish (ASJ) AF: 0.215 AC: 2489 AN: 11598

East Asian (EAS) AF: 0.0326 AC: 427 AN: 13088

South Asian (SAS) AF: 0.162 AC: 10647 AN: 65860

European-Finnish (FIN) AF: 0.356 AC: 11426 AN: 32128

Middle Eastern (MID) AF: 0.176 AC: 499 AN: 2836

European-Non Finnish (NFE) AF: 0.268 AC: 50616 AN: 189208

Other (OTH) AF: 0.231 AC: 3819 AN: 16514

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

African (AFR) AF: 0.0588 AC: 2441 AN: 41484

American (AMR) AF: 0.215 AC: 3276 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 763 AN: 3468

East Asian (EAS) AF: 0.0380 AC: 196 AN: 5160

South Asian (SAS) AF: 0.149 AC: 715 AN: 4814

European-Finnish (FIN) AF: 0.360 AC: 3795 AN: 10554

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18488 AN: 67942

Other (OTH) AF: 0.198 AC: 417 AN: 2104

Alfa AF: 0.250 Hom.: 7135

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
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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