rs752161415
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_018834.6(MATR3):c.2038G>A(p.Asp680Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000743 in 1,614,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
MATR3
NM_018834.6 missense
NM_018834.6 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 6.65
Genes affected
MATR3 (HGNC:6912): (matrin 3) This gene encodes a nuclear matrix protein, which is proposed to stabilize certain messenger RNA species. Mutations of this gene are associated with distal myopathy 2, which often includes vocal cord and pharyngeal weakness. Alternatively spliced transcript variants, including read-through transcripts composed of the upstream small nucleolar RNA host gene 4 (non-protein coding) and matrin 3 gene sequence, have been identified. Pseudogenes of this gene are located on chromosomes 1 and X. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), MATR3. . Gene score misZ 2.7297 (greater than the threshold 3.09). Trascript score misZ 3.9451 (greater than threshold 3.09). GenCC has associacion of gene with amyotrophic lateral sclerosis, distal myopathy with vocal cord weakness, amyotrophic lateral sclerosis type 21.
BP4
Computational evidence support a benign effect (MetaRNN=0.32343638).
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MATR3 | NM_018834.6 | c.2038G>A | p.Asp680Asn | missense_variant | 12/15 | ENST00000394805.8 | NP_061322.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MATR3 | ENST00000394805.8 | c.2038G>A | p.Asp680Asn | missense_variant | 12/15 | 1 | NM_018834.6 | ENSP00000378284.3 | ||
MATR3 | ENST00000394800.6 | c.2038G>A | p.Asp680Asn | missense_variant | 16/19 | 5 | ENSP00000378279.2 | |||
MATR3 | ENST00000502929.5 | c.2038G>A | p.Asp680Asn | missense_variant | 17/20 | 2 | ENSP00000422319.1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251370Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135878
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GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727228
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74348
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Amyotrophic lateral sclerosis type 21 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 21, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 24, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 680 of the MATR3 protein (p.Asp680Asn). This variant is present in population databases (rs752161415, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MATR3-related conditions. ClinVar contains an entry for this variant (Variation ID: 474081). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MATR3 protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Apr 27, 2019 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 16, 2023 | The c.2038G>A (p.D680N) alteration is located in exon 15 (coding exon 11) of the MATR3 gene. This alteration results from a G to A substitution at nucleotide position 2038, causing the aspartic acid (D) at amino acid position 680 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T;T;T;T;T;T;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;.;.;D;.;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;L;.;.;.;L;.;.;.;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N;N;N;N;N;N;.;.
REVEL
Uncertain
Sift
Benign
T;T;D;D;D;T;D;T;D;.;.
Sift4G
Benign
T;T;.;D;D;T;.;T;T;T;D
Polyphen
D;D;.;D;D;D;.;D;.;D;.
Vest4
MutPred
Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);.;Gain of loop (P = 0.069);.;
MVP
MPC
0.52
ClinPred
D
GERP RS
Varity_R
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at