10-29532594-T-C

Variant names:

• chr10-29532594-T-C
• rs1328323
• NM_021738.3:c.1773A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021738.3(SVIL):​c.1773A>G​(p.Lys591Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,613,678 control chromosomes in the GnomAD database, including 139,033 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12024 hom., cov: 32)
  • Exomes 𝑓: 0.41 (127009 hom.)
• Consequence: SVIL NM_021738.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.04
• Publications: 12 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]

SVIL Gene-Disease associations (from GenCC):

• myofibrillar myopathy 10

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

SVIL-AS1 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 10-29532594-T-C is Benign according to our data. Variant chr10-29532594-T-C is described in ClinVar as Benign. ClinVar VariationId is 1260962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVIL	NM_021738.3	c.1773A>G	p.Lys591Lys	synonymous_variant	Exon 8 of 38	ENST00000355867.9	NP_068506.2
SVIL	NM_001323599.2	c.909-422A>G		intron_variant	Intron 9 of 38		NP_001310528.1
SVIL	NM_001323600.1	c.828-1306A>G		intron_variant	Intron 8 of 36		NP_001310529.1
SVIL	NM_003174.3	c.828-1306A>G		intron_variant	Intron 8 of 35		NP_003165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.1773A>G	p.Lys591Lys	synonymous_variant	Exon 8 of 38	1	NM_021738.3	ENSP00000348128.4

Frequencies

GnomAD3 genomes AF: 0.390 AC: 59317 AN: 151916 Hom.: 12020 Cov.: 32

Gnomad AFR AF: 0.347

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.351

Gnomad EAS AF: 0.0808

Gnomad SAS AF: 0.310

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.439

Gnomad OTH AF: 0.394

GnomAD2 exomes AF: 0.370 AC: 92957 AN: 251182 AF XY: 0.372

Gnomad AFR exome AF: 0.348

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.356

Gnomad EAS exome AF: 0.0847

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.444

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.410 AC: 599913 AN: 1461644 Hom.: 127009 Cov.: 70 AF XY: 0.409 AC XY: 297101 AN XY: 727090

African (AFR) AF: 0.346 AC: 11599 AN: 33478

American (AMR) AF: 0.294 AC: 13154 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 9212 AN: 26136

East Asian (EAS) AF: 0.0789 AC: 3133 AN: 39696

South Asian (SAS) AF: 0.319 AC: 27516 AN: 86258

European-Finnish (FIN) AF: 0.455 AC: 24313 AN: 53412

Middle Eastern (MID) AF: 0.337 AC: 1945 AN: 5764

European-Non Finnish (NFE) AF: 0.437 AC: 485936 AN: 1111804

Other (OTH) AF: 0.383 AC: 23105 AN: 60380

GnomAD4 genome AF: 0.390 AC: 59338 AN: 152034 Hom.: 12024 Cov.: 32 AF XY: 0.387 AC XY: 28793 AN XY: 74308

African (AFR) AF: 0.347 AC: 14394 AN: 41472

American (AMR) AF: 0.370 AC: 5663 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.351 AC: 1217 AN: 3466

East Asian (EAS) AF: 0.0812 AC: 418 AN: 5150

South Asian (SAS) AF: 0.310 AC: 1496 AN: 4824

European-Finnish (FIN) AF: 0.444 AC: 4686 AN: 10562

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.439 AC: 29862 AN: 67954

Other (OTH) AF: 0.391 AC: 827 AN: 2116

Alfa AF: 0.414 Hom.: 10196

Bravo AF: 0.382

Asia WGS AF: 0.202 AC: 704 AN: 3478

EpiCase AF: 0.441

EpiControl AF: 0.432

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.8
DANN	Benign	0.62
PhyloP100		1.0
Mutation Taster		=99/1	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: rs1328323; hg19: chr10-29821523; COSMIC: COSV63444852;