4-119023575-T-C

Position:

• chr4-119023575-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_133477.3(SYNPO2):​c.251T>C​(p.Ile84Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SYNPO2 NM_133477.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.66

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNPO2	NM_133477.3	c.251T>C	p.Ile84Thr	missense_variant	2/5	ENST00000307142.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNPO2	ENST00000307142.9	c.251T>C	p.Ile84Thr	missense_variant	2/5	1	NM_133477.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.251T>C (p.I84T) alteration is located in exon 2 (coding exon 2) of the SYNPO2 gene. This alteration results from a T to C substitution at nucleotide position 251, causing the isoleucine (I) at amino acid position 84 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	.;T;.;T;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.7	.;.;M;M;M
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.0	.;D;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.014	.;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.72, 0.38, 0.78	.;P;B;P;.
Vest4		0.77
MutPred		0.77		.;Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);Loss of stability (P = 0.0123);
MVP		0.55
MPC		0.28
ClinPred		0.95	D
GERP RS		5.5
Varity_R		0.31
gMVP		0.62

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-119944730;