10-29495143-G-C

Variant names:

• chr10-29495143-G-C
• rs2368406
• NM_021738.3:c.3703C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.48
• Publications: 31 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 -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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	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.: 22

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

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.: 35 AF XY: 0.775 AC XY: 511595 AN XY: 660370

⚠️ 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.

GnomAD4 genome AF: 0.779 AC: 105104 AN: 134926 Hom.: 40342 Cov.: 22 AF XY: 0.775 AC XY: 50636 AN XY: 65334

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

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

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.000048	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Benign	0.15
Sift	Benign	0.043	D
Sift4G	Benign	0.12	T
Polyphen		0.59	P
Vest4		0.37
MPC		0.73
ClinPred		0.026	T
GERP RS		4.4
Varity_R		0.21
gMVP		0.31
Mutation Taster		=97/3	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: rs2368406; hg19: chr10-29784072; COSMIC: COSV63439228;