rs142286944
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_198576.4(AGRN):c.4977-10A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0257 in 1,612,724 control chromosomes in the GnomAD database, including 655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.018 ( 51 hom., cov: 33)
Exomes 𝑓: 0.026 ( 604 hom. )
Consequence
AGRN
NM_198576.4 splice_polypyrimidine_tract, intron
NM_198576.4 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.00002238
2
Clinical Significance
Conservation
PhyloP100: -1.27
Genes affected
AGRN (HGNC:329): (agrin) This gene encodes one of several proteins that are critical in the development of the neuromuscular junction (NMJ), as identified in mouse knock-out studies. The encoded protein contains several laminin G, Kazal type serine protease inhibitor, and epidermal growth factor domains. Additional post-translational modifications occur to add glycosaminoglycans and disulfide bonds. In one family with congenital myasthenic syndrome affecting limb-girdle muscles, a mutation in this gene was found. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
?
Variant 1-1050417-A-G is Benign according to our data. Variant chr1-1050417-A-G is described in ClinVar as [Benign]. Clinvar id is 263193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-1050417-A-G is described in Lovd as [Benign].
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0185 (2807/152140) while in subpopulation NFE AF= 0.0304 (2068/67924). AF 95% confidence interval is 0.0294. There are 51 homozygotes in gnomad4. There are 1299 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd at 52 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AGRN | NM_198576.4 | c.4977-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000379370.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AGRN | ENST00000379370.7 | c.4977-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_198576.4 | P1 | |||
AGRN | ENST00000620552.4 | c.4563-10A>G | splice_polypyrimidine_tract_variant, intron_variant | 5 | |||||
AGRN | ENST00000651234.1 | c.4662-10A>G | splice_polypyrimidine_tract_variant, intron_variant | ||||||
AGRN | ENST00000652369.1 | c.4662-10A>G | splice_polypyrimidine_tract_variant, intron_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0185 AC: 2812AN: 152022Hom.: 52 Cov.: 33
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GnomAD3 exomes AF: 0.0184 AC: 4542AN: 247310Hom.: 75 AF XY: 0.0191 AC XY: 2576AN XY: 134618
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GnomAD4 exome AF: 0.0265 AC: 38659AN: 1460584Hom.: 604 Cov.: 34 AF XY: 0.0265 AC XY: 19230AN XY: 726614
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GnomAD4 genome ? AF: 0.0185 AC: 2807AN: 152140Hom.: 51 Cov.: 33 AF XY: 0.0175 AC XY: 1299AN XY: 74374
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ClinVar
Significance: Benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 06, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2016 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Congenital myasthenic syndrome 8 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at