NM_021738.3:c.6504G>A

Variant names:

• chr10-29458488-C-T
• rs1887465
• NM_021738.3:c.6504G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021738.3(SVIL):​c.6504G>A​(p.Pro2168Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 1,585,330 control chromosomes in the GnomAD database, including 57,186 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6433 hom., cov: 32)
  • Exomes 𝑓: 0.26 (50753 hom.)
• Consequence: SVIL NM_021738.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.76
• Publications: 18 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-AS1 (HGNC:):

SVIL-AS1 (HGNC:51219): (SVIL antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-29458488-C-T is Benign according to our data. Variant chr10-29458488-C-T is described in ClinVar as Benign. ClinVar VariationId is 1268155.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.523 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SVIL	NM_021738.3	MANE Select	c.6504G>A	p.Pro2168Pro	synonymous	Exon 37 of 38	NP_068506.2	O95425-1
	SVIL	NM_001323599.2		c.5574G>A	p.Pro1858Pro	synonymous	Exon 38 of 39	NP_001310528.1	A0A6I8PIX7
	SVIL	NM_001323600.1		c.5322G>A	p.Pro1774Pro	synonymous	Exon 36 of 37	NP_001310529.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SVIL	ENST00000355867.9	TSL:1 MANE Select	c.6504G>A	p.Pro2168Pro	synonymous	Exon 37 of 38	ENSP00000348128.4	O95425-1
	SVIL	ENST00000375400.7	TSL:1	c.5226G>A	p.Pro1742Pro	synonymous	Exon 35 of 36	ENSP00000364549.3	O95425-2
	SVIL-AS1	ENST00000413405.7	TSL:1	n.212-28667C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42573 AN: 152008 Hom.: 6415 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.339

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.366

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.226

Gnomad OTH AF: 0.257

GnomAD2 exomes AF: 0.312 AC: 70648 AN: 226782 AF XY: 0.307

Gnomad AFR exome AF: 0.302

Gnomad AMR exome AF: 0.452

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.553

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.224

Gnomad OTH exome AF: 0.284

GnomAD4 exome AF: 0.256 AC: 366587 AN: 1433204 Hom.: 50753 Cov.: 34 AF XY: 0.258 AC XY: 183061 AN XY: 710010

African (AFR) AF: 0.292 AC: 9527 AN: 32674

American (AMR) AF: 0.438 AC: 18045 AN: 41168

Ashkenazi Jewish (ASJ) AF: 0.174 AC: 4198 AN: 24082

East Asian (EAS) AF: 0.535 AC: 21036 AN: 39314

South Asian (SAS) AF: 0.359 AC: 29016 AN: 80904

European-Finnish (FIN) AF: 0.328 AC: 17182 AN: 52356

Middle Eastern (MID) AF: 0.233 AC: 1308 AN: 5606

European-Non Finnish (NFE) AF: 0.228 AC: 250611 AN: 1097968

Other (OTH) AF: 0.265 AC: 15664 AN: 59132

GnomAD4 genome AF: 0.280 AC: 42639 AN: 152126 Hom.: 6433 Cov.: 32 AF XY: 0.290 AC XY: 21535 AN XY: 74352

African (AFR) AF: 0.304 AC: 12603 AN: 41486

American (AMR) AF: 0.340 AC: 5206 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2780 AN: 5150

South Asian (SAS) AF: 0.366 AC: 1762 AN: 4818

European-Finnish (FIN) AF: 0.338 AC: 3582 AN: 10590

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15387 AN: 68006

Other (OTH) AF: 0.261 AC: 552 AN: 2112

Alfa AF: 0.246 Hom.: 1508

Bravo AF: 0.283

Asia WGS AF: 0.417 AC: 1447 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.65
DANN	Benign	0.94
PhyloP100		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=74/26	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: rs1887465; hg19: chr10-29747417; COSMIC: COSV63441242; COSMIC: COSV63441242;