rs17756919

Positions:

• chr10-29532160-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000355867.9(SVIL):​c.1851G>A​(p.Val617=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 1,613,406 control chromosomes in the GnomAD database, including 119,486 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10590 hom., cov: 33)
  • Exomes 𝑓: 0.38 (108896 hom.)
• Consequence: SVIL ENST00000355867.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.31

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 10-29532160-C-T is Benign according to our data. Variant chr10-29532160-C-T is described in ClinVar as [Benign]. Clinvar id is 1235948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SVIL	NM_021738.3	c.1851G>A	p.Val617=	synonymous_variant	9/38	ENST00000355867.9	NP_068506.2
SVIL	NM_001323599.2	c.921G>A	p.Val307=	synonymous_variant	10/39		NP_001310528.1
SVIL	NM_001323600.1	c.828-872G>A		intron_variant			NP_001310529.1
SVIL	NM_003174.3	c.828-872G>A		intron_variant			NP_003165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.1851G>A	p.Val617=	synonymous_variant	9/38	1	NM_021738.3	ENSP00000348128	A2
SVIL	ENST00000375400.7	c.828-872G>A		intron_variant		1		ENSP00000364549	P2
SVIL	ENST00000375398.6	c.1851G>A	p.Val617=	synonymous_variant	9/37	5		ENSP00000364547	A2
SVIL	ENST00000674475.1	c.921G>A	p.Val307=	synonymous_variant	10/39			ENSP00000501521	A2

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55868 AN: 151976 Hom.: 10587 Cov.: 33

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.349

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.0806

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.415

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.374

GnomAD3 exomes AF: 0.346 AC: 86665 AN: 250812 Hom.: 16144 AF XY: 0.347 AC XY: 47044 AN XY: 135540

Gnomad AFR exome AF: 0.341

Gnomad AMR exome AF: 0.270

Gnomad ASJ exome AF: 0.323

Gnomad EAS exome AF: 0.0848

Gnomad SAS exome AF: 0.310

Gnomad FIN exome AF: 0.422

Gnomad NFE exome AF: 0.407

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.381 AC: 556056 AN: 1461312 Hom.: 108896 Cov.: 48 AF XY: 0.379 AC XY: 275469 AN XY: 726972

Gnomad4 AFR exome AF: 0.341

Gnomad4 AMR exome AF: 0.281

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.0789

Gnomad4 SAS exome AF: 0.309

Gnomad4 FIN exome AF: 0.421

Gnomad4 NFE exome AF: 0.403

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.367 AC: 55887 AN: 152094 Hom.: 10590 Cov.: 33 AF XY: 0.365 AC XY: 27157 AN XY: 74350

Gnomad4 AFR AF: 0.341

Gnomad4 AMR AF: 0.349

Gnomad4 ASJ AF: 0.321

Gnomad4 EAS AF: 0.0810

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.415

Gnomad4 NFE AF: 0.406

Gnomad4 OTH AF: 0.370

Alfa AF: 0.389 Hom.: 26185

Bravo AF: 0.360

Asia WGS AF: 0.197 AC: 689 AN: 3478

EpiCase AF: 0.408

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.8
DANN	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17756919; hg19: chr10-29821089;