4-119030492-A-T

Position:

• chr4-119030492-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133477.3(SYNPO2):​c.1717A>T​(p.Thr573Ser) 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. 15/21 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. T573A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: SYNPO2 NM_133477.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.488

Genes affected

SYNPO2 (HGNC:17732): (synaptopodin 2) Enables alpha-actinin binding activity and filamin binding activity. Involved in positive regulation of actin filament bundle assembly; positive regulation of cell migration; and regulation of Rho-dependent protein serine/threonine kinase activity. Located in several cellular components, including Z disc; focal adhesion; and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042194426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNPO2	NM_133477.3	c.1717A>T	p.Thr573Ser	missense_variant	4/5	ENST00000307142.9	NP_597734.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNPO2	ENST00000307142.9	c.1717A>T	p.Thr573Ser	missense_variant	4/5	1	NM_133477.3	ENSP00000306015.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 88

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.3
DANN	Benign	0.30
DEOGEN2	Benign	0.0055	.;.;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.063	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.042	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.37	.;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.23	.;T;T;T
Sift4G	Benign	0.65	T;T;T;T
Polyphen		0.0020, 0.0	.;B;B;.
Vest4		0.044
MutPred		0.13		.;Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);
MVP		0.043
MPC		0.072
ClinPred		0.073	T
GERP RS		1.9
Varity_R		0.037
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7698598; hg19: chr4-119951647;