rs9664986

Variant names:

• chr10-29581095-A-G
• rs9664986
• NM_021738.3:c.-200-11783T>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.-200-11783T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 152,258 control chromosomes in the GnomAD database, including 1,720 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 0.15 (1720 hom., cov: 33)
• Consequence: SVIL NM_021738.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 2 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVIL	NM_021738.3	c.-200-11783T>C		intron_variant	Intron 1 of 37	ENST00000355867.9	NP_068506.2
SVIL	NM_001323599.2	c.-200-11783T>C		intron_variant	Intron 3 of 38		NP_001310528.1
SVIL	NM_001323600.1	c.-200-11783T>C		intron_variant	Intron 3 of 36		NP_001310529.1
SVIL	NM_003174.3	c.-200-11783T>C		intron_variant	Intron 3 of 35		NP_003165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.-200-11783T>C		intron_variant	Intron 1 of 37	1	NM_021738.3	ENSP00000348128.4

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22383 AN: 152140 Hom.: 1710 Cov.: 33

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.150

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

GnomAD4 genome AF: 0.147 AC: 22437 AN: 152258 Hom.: 1720 Cov.: 33 AF XY: 0.148 AC XY: 11025 AN XY: 74440

African (AFR) AF: 0.130 AC: 5392 AN: 41560

American (AMR) AF: 0.226 AC: 3452 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3472

East Asian (EAS) AF: 0.171 AC: 883 AN: 5174

South Asian (SAS) AF: 0.147 AC: 710 AN: 4828

European-Finnish (FIN) AF: 0.137 AC: 1453 AN: 10608

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.143 AC: 9757 AN: 68004

Other (OTH) AF: 0.155 AC: 328 AN: 2112

Alfa AF: 0.146 Hom.: 1189

Bravo AF: 0.153

Asia WGS AF: 0.161 AC: 557 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	4.6
DANN	Benign	0.72
PhyloP100		0.27
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: rs9664986; hg19: chr10-29870024;