NM_021738.3:c.3703C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021738.3(SVIL):c.3703C>G(p.Pro1235Ala) variant causes a missense change. The variant allele was found at a frequency of 0.776 in 1,458,006 control chromosomes in the GnomAD database, including 431,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.78 ( 40342 hom., cov: 22)

Exomes 𝑓: 0.78 ( 391116 hom. )

Consequence

SVIL
NM_021738.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 5.48

Publications

31 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.7830894E-5).

BP6

Variant 10-29495143-G-C is Benign according to our data. Variant chr10-29495143-G-C is described in ClinVar as Benign. ClinVar VariationId is 1174340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.821 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SVIL	NM_021738.3	MANE Select	c.3703C>G	p.Pro1235Ala	missense	Exon 19 of 38	NP_068506.2
SVIL	NM_001323599.2		c.2773C>G	p.Pro925Ala	missense	Exon 20 of 39	NP_001310528.1
SVIL	NM_001323600.1		c.2521C>G	p.Pro841Ala	missense	Exon 18 of 37	NP_001310529.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SVIL	ENST00000355867.9	TSL:1 MANE Select	c.3703C>G	p.Pro1235Ala	missense	Exon 19 of 38	ENSP00000348128.4
SVIL	ENST00000375400.7	TSL:1	c.2425C>G	p.Pro809Ala	missense	Exon 17 of 36	ENSP00000364549.3
SVIL	ENST00000860295.1		c.3829C>G	p.Pro1277Ala	missense	Exon 21 of 40	ENSP00000530354.1

Frequencies

GnomAD3 genomes

AF:

0.779

AC:

105022

AN:

134814

Hom.:

40313

Cov.:

show subpopulations

Gnomad AFR

AF:

0.830

Gnomad AMI

AF:

0.734

Gnomad AMR

AF:

0.726

Gnomad ASJ

AF:

0.776

Gnomad EAS

AF:

0.604

Gnomad SAS

AF:

0.707

Gnomad FIN

AF:

0.799

Gnomad MID

AF:

0.732

Gnomad NFE

AF:

0.781

Gnomad OTH

AF:

0.768

GnomAD2 exomes

AF:

0.764

AC:

176102

AN:

230516

AF XY:

0.764

show subpopulations

Gnomad AFR exome

AF:

0.825

Gnomad AMR exome

AF:

0.677

Gnomad ASJ exome

AF:

0.798

Gnomad EAS exome

AF:

0.644

Gnomad FIN exome

AF:

0.814

Gnomad NFE exome

AF:

0.790

Gnomad OTH exome

AF:

0.777

GnomAD4 exome

AF:

0.776

AC:

1026251

AN:

1323080

Hom.:

391116

Cov.:

AF XY:

0.775

AC XY:

511595

AN XY:

660370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.834

AC:

24814

AN:

29752

American (AMR)

AF:

0.664

AC:

26072

AN:

39264

Ashkenazi Jewish (ASJ)

AF:

0.786

AC:

19410

AN:

24692

East Asian (EAS)

AF:

0.634

AC:

22517

AN:

35528

South Asian (SAS)

AF:

0.730

AC:

58152

AN:

79612

European-Finnish (FIN)

AF:

0.808

AC:

41761

AN:

51668

Middle Eastern (MID)

AF:

0.726

AC:

3474

AN:

4788

European-Non Finnish (NFE)

AF:

0.785

AC:

787446

AN:

1002642

Other (OTH)

AF:

0.773

AC:

42605

AN:

55134

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.393

Heterozygous variant carriers

8419

16837

25256

33674

42093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18282

36564

54846

73128

91410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.779

AC:

105104

AN:

134926

Hom.:

40342

Cov.:

AF XY:

0.775

AC XY:

50636

AN XY:

65334

show subpopulations

African (AFR)

AF:

0.830

AC:

25873

AN:

31174

American (AMR)

AF:

0.726

AC:

9826

AN:

13538

Ashkenazi Jewish (ASJ)

AF:

0.776

AC:

2591

AN:

3340

East Asian (EAS)

AF:

0.603

AC:

2753

AN:

4564

South Asian (SAS)

AF:

0.705

AC:

2998

AN:

4250

European-Finnish (FIN)

AF:

0.799

AC:

7588

AN:

9502

Middle Eastern (MID)

AF:

0.738

AC:

211

AN:

286

European-Non Finnish (NFE)

AF:

0.781

AC:

51180

AN:

65512

Other (OTH)

AF:

0.765

AC:

1448

AN:

1894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

771

1542

2313

3084

3855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

780

1560

2340

3120

3900

<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:

0.777

Hom.:

7602

ExAC

AF:

0.744

AC:

90203

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

MetaRNN

Benign

0.000048

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

PhyloP100

5.5

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.15

Sift

Benign

0.043

Sift4G

Benign

0.12

Polyphen

0.59

Vest4

0.37

MPC

0.73

ClinPred

0.026

GERP RS

4.4

Varity_R

0.21

gMVP

0.31

Mutation Taster

=97/3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over