10-73646785-G-T

Variant names:

• chr10-73646785-G-T
• rs770357363
• NM_001114133.3:c.2867C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001114133.3(SYNPO2L):​c.2867C>A​(p.Pro956His) variant causes a missense change. The variant allele was found at a frequency of 0.000000729 in 1,372,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P956L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: SYNPO2L NM_001114133.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001114133.3. 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
	SYNPO2L	NM_001114133.3	MANE Select	c.2867C>A	p.Pro956His	missense	Exon 4 of 4	NP_001107605.1	Q9H987-1
	SYNPO2L	NM_024875.5		c.2195C>A	p.Pro732His	missense	Exon 2 of 2	NP_079151.2	Q9H987-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNPO2L	ENST00000394810.3	TSL:1 MANE Select	c.2867C>A	p.Pro956His	missense	Exon 4 of 4	ENSP00000378289.2	Q9H987-1
	SYNPO2L	ENST00000372873.8	TSL:1	c.2195C>A	p.Pro732His	missense	Exon 2 of 2	ENSP00000361964.4	Q9H987-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1372524 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 673712

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30388

American (AMR) AF: 0.00 AC: 0 AN: 29578

Ashkenazi Jewish (ASJ) AF: 0.0000496 AC: 1 AN: 20170

East Asian (EAS) AF: 0.00 AC: 0 AN: 38974

South Asian (SAS) AF: 0.00 AC: 0 AN: 70396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5338

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071124

Other (OTH) AF: 0.00 AC: 0 AN: 56412

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Uncertain	-0.094	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.3	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.48		Gain of MoRF binding (P = 0.0666)
MVP		0.95
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.73
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs770357363; hg19: chr10-75406543;