X-47572946-C-T

Variant names:

• chrX-47572946-C-T
• NM_006950.3:c.2036G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Moderate BP6_Moderate

The NM_006950.3(SYN1):​c.2036G>A​(p.Arg679Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a modified_residue Asymmetric dimethylarginine (size 0) in uniprot entity SYN1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2305114).
• BP6: Variant X-47572946-C-T is Benign according to our data. Variant chrX-47572946-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3451834.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.2036G>A	p.Arg679Lys	missense_variant	Exon 13 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1998G>A	p.Gln666Gln	synonymous_variant	Exon 13 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.2036G>A	p.Arg679Lys	missense_variant	Exon 13 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1998G>A	p.Gln666Gln	synonymous_variant	Exon 13 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.86G>A	p.Arg29Lys	missense_variant	Exon 2 of 2	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Aug 20, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;.
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.048
Sift	Benign	0.068	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.63	P;.
Vest4		0.28
MutPred		0.26		Gain of ubiquitination at R679 (P = 0.0051);.;
MVP		0.59
MPC		1.8
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: chrX-47432345;