X-47574760-C-T

Position:

• chrX-47574760-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006950.3(SYN1):​c.1321G>A​(p.Ala441Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000027 in 1,073,470 control chromosomes in the GnomAD database, including 1 homozygotes. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000027 (1 hom. 14 hem.)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.23

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05308047).
• BS2: High Hemizygotes in GnomAdExome4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1321G>A	p.Ala441Thr	missense_variant	11/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1321G>A	p.Ala441Thr	missense_variant	11/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1321G>A	p.Ala441Thr	missense_variant	11/13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1321G>A	p.Ala441Thr	missense_variant	11/13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.-3G>A		upstream_gene_variant		5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000764 AC: 1 AN: 130933 Hom.: 0 AF XY: 0.0000235 AC XY: 1 AN XY: 42639

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000650

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000270 AC: 29 AN: 1073470 Hom.: 1 Cov.: 31 AF XY: 0.0000400 AC XY: 14 AN XY: 349620

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: 0.000528

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000443

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000444 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.1321G>A (p.Ala441Thr) variant in SYN1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency 0.0007% in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as Uncertain Significance. The amino acid Ala at position 441 is changed to a Thr changing protein sequence and it might alter its composition and physicochemical properties. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Ala441Thr in SYN1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. The observed variant was detected in hemizygous state in the brother. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2021	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SYN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 436901). This variant is present in population databases (rs772106134, ExAC 0.05%). This sequence change replaces alanine with threonine at codon 441 of the SYN1 protein (p.Ala441Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 19, 2017

- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2018

The p.A441T variant (also known as c.1321G>A), located in coding exon 11 of the SYN1 gene, results from a G to A substitution at nucleotide position 1321. The alanine at codon 441 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.18	T;.
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.62	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.10	N;N
REVEL	Benign	0.021
Sift	Benign	0.28	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.010	B;B
Vest4		0.084
MutPred		0.30		Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP		0.27
MPC		0.66
ClinPred		0.24	T
GERP RS		4.5
Varity_R		0.13
gMVP		0.15

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: rs772106134; hg19: chrX-47434159;