NM_021738.3:c.3626C>G

Variant names:

• chr10-29499154-G-C
• rs767673427
• NM_021738.3:c.3626C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_021738.3(SVIL):​c.3626C>G​(p.Ser1209Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1209L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SVIL NM_021738.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.75

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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-29499154-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVIL	NM_021738.3	c.3626C>G	p.Ser1209Trp	missense_variant	Exon 18 of 38	ENST00000355867.9	NP_068506.2
SVIL	NM_001323599.2	c.2696C>G	p.Ser899Trp	missense_variant	Exon 19 of 39		NP_001310528.1
SVIL	NM_001323600.1	c.2444C>G	p.Ser815Trp	missense_variant	Exon 17 of 37		NP_001310529.1
SVIL	NM_003174.3	c.2348C>G	p.Ser783Trp	missense_variant	Exon 16 of 36		NP_003165.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVIL	ENST00000355867.9	c.3626C>G	p.Ser1209Trp	missense_variant	Exon 18 of 38	1	NM_021738.3	ENSP00000348128.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249914 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461748 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	.;.;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	.;.;M
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.86
MutPred		0.35		.;.;Loss of disorder (P = 0.0037);
MVP		0.41
MPC		1.0
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.84
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs767673427; hg19: chr10-29788083;