chrX-47574756-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006950.3(SYN1):c.1325T>C(p.Leu442Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,186,149 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L442L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., 16 hem., cov: 23)

Exomes 𝑓: 0.000053 ( 0 hom. 12 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.976

Publications

1 publications found

Variant links:

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

SYN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01687032).

BP6

Variant X-47574756-A-G is Benign according to our data. Variant chrX-47574756-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193940.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000528 (59/111687) while in subpopulation AFR AF = 0.00192 (59/30755). AF 95% confidence interval is 0.00153. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 16 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006950.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1325T>C	p.Leu442Pro	missense	Exon 11 of 13	NP_008881.2
	SYN1	NM_133499.2		c.1325T>C	p.Leu442Pro	missense	Exon 11 of 13	NP_598006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1325T>C	p.Leu442Pro	missense	Exon 11 of 13	ENSP00000295987.7
SYN1	ENST00000340666.5	TSL:1	c.1325T>C	p.Leu442Pro	missense	Exon 11 of 13	ENSP00000343206.4
SYN1	ENST00000640721.1	TSL:5	c.2T>C	p.Leu1?	start_lost	Exon 1 of 2	ENSP00000492857.1

Frequencies

GnomAD3 genomes

AF:

0.000520

AC:

AN:

111639

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00189

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000128

AC:

AN:

132407

AF XY:

0.000139

show subpopulations

Gnomad AFR exome

AF:

0.00205

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000530

AC:

AN:

1074462

Hom.:

Cov.:

AF XY:

0.0000343

AC XY:

AN XY:

350126

show subpopulations

African (AFR)

AF:

0.00183

AC:

AN:

26248

American (AMR)

AF:

0.0000329

AC:

AN:

30432

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18814

East Asian (EAS)

AF:

0.00

AC:

AN:

29464

South Asian (SAS)

AF:

0.00

AC:

AN:

51166

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38723

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3871

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

830552

Other (OTH)

AF:

0.000177

AC:

AN:

45192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000528

AC:

AN:

111687

Hom.:

Cov.:

AF XY:

0.000472

AC XY:

AN XY:

33931

show subpopulations

African (AFR)

AF:

0.00192

AC:

AN:

30755

American (AMR)

AF:

0.00

AC:

AN:

10758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3494

South Asian (SAS)

AF:

0.00

AC:

AN:

2664

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6094

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52864

Other (OTH)

AF:

0.00

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.000559

ESP6500AA

AF:

0.000548

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000885

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.35

LIST_S2

Benign

0.39

M_CAP

Benign

0.028

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.98

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.65

REVEL

Benign

0.021

Sift

Benign

0.15

Sift4G

Benign

0.34

Polyphen

0.0

Vest4

0.16

MVP

0.21

MPC

1.1

ClinPred

0.034

GERP RS

1.4

PromoterAI

0.12

Neutral

(source)

Varity_R

0.16

gMVP

0.35

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over