NM_021738.3:c.6558+48G>A

Variant names:

• chr10-29458386-C-T
• rs2368409
• NM_021738.3:c.6558+48G>A

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.6558+48G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 1,610,188 control chromosomes in the GnomAD database, including 19,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1683 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18055 hom.)
• Consequence: SVIL NM_021738.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.57
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-29458386-C-T is Benign according to our data. Variant chr10-29458386-C-T is described in ClinVar as Benign. ClinVar VariationId is 1228692.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.287 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.6558+48G>A		intron	N/A	NP_068506.2	O95425-1
	SVIL	NM_001323599.2		c.5628+48G>A		intron	N/A	NP_001310528.1	A0A6I8PIX7
	SVIL	NM_001323600.1		c.5376+48G>A		intron	N/A	NP_001310529.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SVIL	ENST00000355867.9	TSL:1 MANE Select	c.6558+48G>A		intron	N/A	ENSP00000348128.4	O95425-1
	SVIL	ENST00000375400.7	TSL:1	c.5280+48G>A		intron	N/A	ENSP00000364549.3	O95425-2
	SVIL-AS1	ENST00000413405.7	TSL:1	n.212-28769C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21610 AN: 152018 Hom.: 1677 Cov.: 33

Gnomad AFR AF: 0.0993

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.163

Gnomad ASJ AF: 0.106

Gnomad EAS AF: 0.299

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.137

GnomAD2 exomes AF: 0.163 AC: 39586 AN: 242912 AF XY: 0.163

Gnomad AFR exome AF: 0.0988

Gnomad AMR exome AF: 0.210

Gnomad ASJ exome AF: 0.0972

Gnomad EAS exome AF: 0.298

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.152 AC: 221584 AN: 1458052 Hom.: 18055 Cov.: 32 AF XY: 0.153 AC XY: 110974 AN XY: 725138

African (AFR) AF: 0.0966 AC: 3225 AN: 33374

American (AMR) AF: 0.216 AC: 9572 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2783 AN: 25884

East Asian (EAS) AF: 0.312 AC: 12345 AN: 39594

South Asian (SAS) AF: 0.184 AC: 15738 AN: 85724

European-Finnish (FIN) AF: 0.203 AC: 10819 AN: 53314

Middle Eastern (MID) AF: 0.128 AC: 732 AN: 5732

European-Non Finnish (NFE) AF: 0.142 AC: 157212 AN: 1109956

Other (OTH) AF: 0.152 AC: 9158 AN: 60220

GnomAD4 genome AF: 0.142 AC: 21628 AN: 152136 Hom.: 1683 Cov.: 33 AF XY: 0.146 AC XY: 10868 AN XY: 74362

African (AFR) AF: 0.0993 AC: 4127 AN: 41556

American (AMR) AF: 0.164 AC: 2498 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.106 AC: 369 AN: 3470

East Asian (EAS) AF: 0.299 AC: 1545 AN: 5160

South Asian (SAS) AF: 0.179 AC: 864 AN: 4822

European-Finnish (FIN) AF: 0.196 AC: 2077 AN: 10588

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.144 AC: 9768 AN: 67960

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.0948 Hom.: 166

Bravo AF: 0.139

Asia WGS AF: 0.229 AC: 793 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	-0.90
CADD	Benign	0.043
DANN	Benign	0.76
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2368409; hg19: chr10-29747315; COSMIC: COSV63448121;