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GeneBe

19-17618930-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_001080421.3(UNC13A):c.4305G>A(p.Glu1435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,614,030 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)
Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

UNC13A
NM_001080421.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0750
Variant links:
Genes affected
UNC13A (HGNC:23150): (unc-13 homolog A) This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.4).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 19-17618930-C-T is Benign according to our data. Variant chr19-17618930-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 728245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.075 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 310 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
UNC13ANM_001080421.3 linkuse as main transcriptc.4305G>A p.Glu1435= synonymous_variant 39/44 ENST00000519716.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UNC13AENST00000519716.7 linkuse as main transcriptc.4305G>A p.Glu1435= synonymous_variant 39/445 NM_001080421.3 A2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00204
AC:
310
AN:
152210
Hom.:
2
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00644
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0127
Gnomad NFE
AF:
0.000353
Gnomad OTH
AF:
0.00192
GnomAD3 exomes
AF:
0.000662
AC:
165
AN:
249274
Hom.:
1
AF XY:
0.000525
AC XY:
71
AN XY:
135230
show subpopulations
Gnomad AFR exome
AF:
0.00646
Gnomad AMR exome
AF:
0.000666
Gnomad ASJ exome
AF:
0.000298
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000301
Gnomad OTH exome
AF:
0.000330
GnomAD4 exome
AF:
0.000393
AC:
575
AN:
1461702
Hom.:
4
Cov.:
33
AF XY:
0.000378
AC XY:
275
AN XY:
727136
show subpopulations
Gnomad4 AFR exome
AF:
0.00675
Gnomad4 AMR exome
AF:
0.00110
Gnomad4 ASJ exome
AF:
0.000344
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000164
Gnomad4 OTH exome
AF:
0.000911
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00202
AC:
308
AN:
152328
Hom.:
2
Cov.:
32
AF XY:
0.00201
AC XY:
150
AN XY:
74484
show subpopulations
Gnomad4 AFR
AF:
0.00642
Gnomad4 AMR
AF:
0.000719
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000353
Gnomad4 OTH
AF:
0.00190
Alfa
AF:
0.000945
Hom.:
0
Bravo
AF:
0.00232
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.000818
EpiControl
AF:
0.000296

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

UNC13A-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 27, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
Cadd
Benign
5.6
Dann
Benign
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs191793337; hg19: chr19-17729739; API