10-29545069-A-G

Variant names:

• chr10-29545069-A-G
• rs2368393
• NM_021738.3:c.827+5528T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_021738.3(SVIL):​c.827+5528T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 533,780 control chromosomes in the GnomAD database, including 22,724 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 (7075 hom., cov: 31)
  • Exomes 𝑓: 0.28 (15649 hom.)
• Consequence: SVIL NM_021738.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0990
• Publications: 22 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]

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]

SVIL-AS1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021738.3. 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
	SVIL	NM_021738.3	MANE Select	c.827+5528T>C		intron	N/A	NP_068506.2	O95425-1
	SVIL	NM_001323599.2		c.827+5528T>C		intron	N/A	NP_001310528.1	A0A6I8PIX7
	SVIL	NM_001323600.1		c.827+5528T>C		intron	N/A	NP_001310529.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SVIL	ENST00000355867.9	TSL:1 MANE Select	c.827+5528T>C		intron	N/A	ENSP00000348128.4	O95425-1
	SVIL	ENST00000375400.7	TSL:1	c.827+5528T>C		intron	N/A	ENSP00000364549.3	O95425-2
	SVIL	ENST00000860295.1		c.827+5528T>C		intron	N/A	ENSP00000530354.1

Frequencies

GnomAD3 genomes AF: 0.302 AC: 45824 AN: 151708 Hom.: 7069 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.277

GnomAD2 exomes AF: 0.287 AC: 71775 AN: 250498 AF XY: 0.282

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.340

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.257

Gnomad OTH exome AF: 0.270

GnomAD4 exome AF: 0.281 AC: 107388 AN: 381954 Hom.: 15649 Cov.: 0 AF XY: 0.281 AC XY: 61032 AN XY: 217450

African (AFR) AF: 0.385 AC: 4046 AN: 10506

American (AMR) AF: 0.303 AC: 10985 AN: 36278

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 1945 AN: 11734

East Asian (EAS) AF: 0.333 AC: 4379 AN: 13162

South Asian (SAS) AF: 0.310 AC: 20664 AN: 66650

European-Finnish (FIN) AF: 0.311 AC: 9992 AN: 32116

Middle Eastern (MID) AF: 0.186 AC: 531 AN: 2854

European-Non Finnish (NFE) AF: 0.262 AC: 50253 AN: 191938

Other (OTH) AF: 0.275 AC: 4593 AN: 16716

GnomAD4 genome AF: 0.302 AC: 45848 AN: 151826 Hom.: 7075 Cov.: 31 AF XY: 0.304 AC XY: 22553 AN XY: 74220

African (AFR) AF: 0.380 AC: 15733 AN: 41390

American (AMR) AF: 0.293 AC: 4474 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 557 AN: 3466

East Asian (EAS) AF: 0.320 AC: 1642 AN: 5138

South Asian (SAS) AF: 0.317 AC: 1520 AN: 4802

European-Finnish (FIN) AF: 0.302 AC: 3184 AN: 10542

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17635 AN: 67912

Other (OTH) AF: 0.276 AC: 581 AN: 2108

Alfa AF: 0.276 Hom.: 10722

Bravo AF: 0.305

Asia WGS AF: 0.344 AC: 1195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	3.0
DANN	Benign	0.50
PhyloP100		0.099
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: rs2368393; hg19: chr10-29833998; COSMIC: COSV63441407;