10-73648382-G-A

Variant names:

• chr10-73648382-G-A
• rs139351387
• NM_001114133.3:c.1270C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001114133.3(SYNPO2L):​c.1270C>T​(p.Arg424Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,454,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R424G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYNPO2L NM_001114133.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

Genes affected

SYNPO2L (HGNC:23532): (synaptopodin 2 like) Predicted to enable actin binding activity. Predicted to be involved in several processes, including positive regulation of Rho protein signal transduction; positive regulation of stress fiber assembly; and sarcomere organization. Located in cell junction; cytosol; and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29197037).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNPO2L	NM_001114133.3	c.1270C>T	p.Arg424Trp	missense_variant	Exon 4 of 4	ENST00000394810.3	NP_001107605.1
SYNPO2L	NM_024875.5	c.598C>T	p.Arg200Trp	missense_variant	Exon 2 of 2		NP_079151.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNPO2L	ENST00000394810.3	c.1270C>T	p.Arg424Trp	missense_variant	Exon 4 of 4	1	NM_001114133.3	ENSP00000378289.2
SYNPO2L	ENST00000372873.8	c.598C>T	p.Arg200Trp	missense_variant	Exon 2 of 2	1		ENSP00000361964.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454798 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 724138

Gnomad4 AFR exome AF: 0.0000299

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1270C>T (p.R424W) alteration is located in exon 4 (coding exon 4) of the SYNPO2L gene. This alteration results from a C to T substitution at nucleotide position 1270, causing the arginine (R) at amino acid position 424 to be replaced by a tryptophan (W). 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	Benign	0.098
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	.;T
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.29	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;M
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.7	D;D
REVEL	Benign	0.068
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;D
Vest4		0.13
MVP		0.63
MPC		0.39
ClinPred		0.97	D
GERP RS		4.4
Varity_R		0.28
gMVP		0.44

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: rs139351387; hg19: chr10-75408140;