chrX-47619353-A-T

Position:

• chrX-47619353-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006950.3(SYN1):​c.376T>A​(p.Trp126Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: SYN1 NM_006950.3 missense, splice_region
• Scores: Splicing: ADA: 0.007689
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.19

Genes affected

SYN1 (HGNC:11494): (synapsin I) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ENSG00000283743 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.376T>A	p.Trp126Arg	missense_variant, splice_region_variant	1/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.376T>A	p.Trp126Arg	missense_variant, splice_region_variant	1/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.376T>A	p.Trp126Arg	missense_variant, splice_region_variant	1/13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.376T>A	p.Trp126Arg	missense_variant, splice_region_variant	1/13	1		ENSP00000343206.4
SYN1	ENST00000639776.1	c.34T>A	p.Trp12Arg	missense_variant, splice_region_variant	1/6	3		ENSP00000492521.1
ENSG00000283743	ENST00000638776.2	n.2833+3737T>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

NeuroMeGen, Hospital Clinico Santiago de Compostela

Jan 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Benign	0.96
DEOGEN2	Pathogenic	0.86	D;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-11	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.80	P;B
Vest4		0.94
MutPred		0.91		Gain of disorder (P = 0.0092);Gain of disorder (P = 0.0092);
MVP		0.97
MPC		1.8
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.94
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0077
dbscSNV1_RF	Benign	0.20
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: rs1556861783; hg19: chrX-47478752;