X-47574317-C-T

Variant names:

• chrX-47574317-C-T
• rs913197225
• NM_006950.3:c.1667G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006950.3(SYN1):​c.1667G>A​(p.Arg556His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 960,895 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign 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. R556L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000031 (0 hom. 1 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.44
• Publications: 0 publications found

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]

SYN1 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3153513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1667G>A	p.Arg556His	missense_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1667G>A	p.Arg556His	missense_variant	Exon 12 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1667G>A	p.Arg556His	missense_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1667G>A	p.Arg556His	missense_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.70+371G>A		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000312 AC: 3 AN: 960895 Hom.: 0 Cov.: 32 AF XY: 0.00000331 AC XY: 1 AN XY: 301779

⚠️ 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: 20226

American (AMR) AF: 0.00 AC: 0 AN: 16198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15736

East Asian (EAS) AF: 0.00 AC: 0 AN: 21486

South Asian (SAS) AF: 0.00 AC: 0 AN: 38378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2589

European-Non Finnish (NFE) AF: 0.00000384 AC: 3 AN: 781682

Other (OTH) AF: 0.00 AC: 0 AN: 40328

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.85	D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N;N
PhyloP100		2.4
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.090
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.16	T;T
Polyphen		1.0	D;D
Vest4		0.27
MutPred		0.29		Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.49
MPC		2.7
ClinPred		0.77	D
GERP RS		4.5
PromoterAI		-0.022	Neutral
Varity_R		0.20
gMVP		0.30
Mutation Taster		=82/18	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: rs913197225; hg19: chrX-47433716;