Genetic Variant SVIL:c.4193-585A>C (chr10-29489341-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_021738.3(SVIL):c.4193-585A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0949 in 152,252 control chromosomes in the GnomAD database, including 867 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 0.095 ( 867 hom., cov: 32)

Consequence

SVIL
NM_021738.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.502

Publications

3 publications found

Variant links:

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 links:

SVIL-AS1 (HGNC:):

SVIL-AS1 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
SVIL	NM_021738.3 link	c.4193-585A>C	intron_variant	Intron 22 of 37	ENST00000355867.9	NP_068506.2	O95425-1Q569J5
SVIL	NM_001323599.2 link	c.3263-585A>C	intron_variant	Intron 23 of 38		NP_001310528.1	A0A6I8PIX7
SVIL	NM_001323600.1 link	c.3011-585A>C	intron_variant	Intron 21 of 36		NP_001310529.1
SVIL	NM_003174.3 link	c.2915-585A>C	intron_variant	Intron 20 of 35		NP_003165.2	O95425-2Q569J5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9 link	c.4193-585A>C		intron_variant	Intron 22 of 37	1	NM_021738.3	ENSP00000348128.4		O95425-1

Frequencies

GnomAD3 genomes

AF:

0.0950

AC:

14459

AN:

152134

Hom.:

868

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0471

Gnomad AMI

AF:

0.163

Gnomad AMR

AF:

0.0854

Gnomad ASJ

AF:

0.0504

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0290

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.0538

Gnomad NFE

AF:

0.132

Gnomad OTH

AF:

0.0870

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0949

AC:

14456

AN:

152252

Hom.:

867

Cov.:

AF XY:

0.0957

AC XY:

7123

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0470

AC:

1951

AN:

41532

American (AMR)

AF:

0.0853

AC:

1306

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0504

AC:

175

AN:

3470

East Asian (EAS)

AF:

0.000578

AC:

AN:

5186

South Asian (SAS)

AF:

0.0288

AC:

139

AN:

4826

European-Finnish (FIN)

AF:

0.146

AC:

1542

AN:

10596

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.132

AC:

8992

AN:

68012

Other (OTH)

AF:

0.0861

AC:

182

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

651

1301

1952

2602

3253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

336

504

672

840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.117

Hom.:

1248

Bravo

AF:

0.0882

Asia WGS

AF:

0.0190

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.52

(source)

DANN

Benign

0.53

PhyloP100

-0.50

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over