10-73647992-C-T

Variant names:

• chr10-73647992-C-T
• rs1465565690
• NM_001114133.3:c.1660G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001114133.3(SYNPO2L):​c.1660G>A​(p.Ala554Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,412,422 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SYNPO2L NM_001114133.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.270

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2056253).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNPO2L	NM_001114133.3	c.1660G>A	p.Ala554Thr	missense_variant	Exon 4 of 4	ENST00000394810.3	NP_001107605.1
SYNPO2L	NM_024875.5	c.988G>A	p.Ala330Thr	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.1660G>A	p.Ala554Thr	missense_variant	Exon 4 of 4	1	NM_001114133.3	ENSP00000378289.2
SYNPO2L	ENST00000372873.8	c.988G>A	p.Ala330Thr	missense_variant	Exon 2 of 2	1		ENSP00000361964.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000142 AC: 20 AN: 1412422 Hom.: 0 Cov.: 35 AF XY: 0.0000158 AC XY: 11 AN XY: 698102

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: 0.0000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000612 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1660G>A (p.A554T) alteration is located in exon 4 (coding exon 4) of the SYNPO2L gene. This alteration results from a G to A substitution at nucleotide position 1660, causing the alanine (A) at amino acid position 554 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	Benign	0.14
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0044	.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.54	N;N
REVEL	Benign	0.092
Sift	Uncertain	0.019	D;D
Sift4G	Benign	0.064	T;T
Polyphen		0.86	P;P
Vest4		0.30
MutPred		0.17		.;Gain of glycosylation at A554 (P = 0.0041);
MVP		0.62
MPC		1.1
ClinPred		0.92	D
GERP RS		5.0
Varity_R		0.13
gMVP		0.41

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: rs1465565690; hg19: chr10-75407750; COSMIC: COSV65739321;