chr10-29458291-C-A

Variant names:

• chr10-29458291-C-A
• rs147771631
• NM_021738.3:c.6601G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021738.3(SVIL):​c.6601G>T​(p.Ala2201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A2201T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SVIL NM_021738.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.741
• Publications: 1 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053919196).

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.6601G>T	p.Ala2201Ser	missense	Exon 38 of 38	NP_068506.2	O95425-1
	SVIL	NM_001323599.2		c.5671G>T	p.Ala1891Ser	missense	Exon 39 of 39	NP_001310528.1	A0A6I8PIX7
	SVIL	NM_001323600.1		c.5419G>T	p.Ala1807Ser	missense	Exon 37 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.6601G>T	p.Ala2201Ser	missense	Exon 38 of 38	ENSP00000348128.4	O95425-1
	SVIL	ENST00000375400.7	TSL:1	c.5323G>T	p.Ala1775Ser	missense	Exon 36 of 36	ENSP00000364549.3	O95425-2
	SVIL-AS1	ENST00000413405.7	TSL:1	n.212-28864C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.5
DANN	Benign	0.84
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.53	N
PhyloP100		0.74
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.59	N
REVEL	Benign	0.063
Sift	Benign	0.77	T
Sift4G	Benign	0.92	T
Polyphen		0.0090	B
Vest4		0.069
MutPred		0.49		Loss of catalytic residue at A2201 (P = 0.0039)
MVP		0.11
MPC		0.22
ClinPred		0.025	T
GERP RS		0.23
Varity_R		0.021
gMVP		0.31
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs147771631; hg19: chr10-29747220;