rs587777300

Variant names:

• chr5-139307759-T-A
• rs587777300
• NM_018834.6:c.344T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-139307759-T-A
• chr5-139307759-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018834.6(MATR3):​c.344T>A​(p.Phe115Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F115C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.23
• Publications: 32 publications found

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]

MATR3 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 21

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• distal myopathy with vocal cord weakness

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018834.6. 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
	MATR3	NM_018834.6	MANE Select	c.344T>A	p.Phe115Tyr	missense	Exon 2 of 15	NP_061322.2
	MATR3	NM_001400441.1		c.344T>A	p.Phe115Tyr	missense	Exon 3 of 16	NP_001387370.1
	MATR3	NM_001400442.1		c.344T>A	p.Phe115Tyr	missense	Exon 5 of 18	NP_001387371.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATR3	ENST00000394805.8	TSL:1 MANE Select	c.344T>A	p.Phe115Tyr	missense	Exon 2 of 15	ENSP00000378284.3
	MATR3	ENST00000502929.5	TSL:2	c.344T>A	p.Phe115Tyr	missense	Exon 7 of 20	ENSP00000422319.1
	MATR3	ENST00000618441.5	TSL:1	c.344T>A	p.Phe115Tyr	missense	Exon 2 of 15	ENSP00000482895.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.4	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.020	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.62
MutPred		0.38		Gain of catalytic residue at F115 (P = 0.064)
MVP		0.89
MPC		2.1
ClinPred		0.79	D
GERP RS		5.7
PromoterAI		0.0076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.57
Mutation Taster		=47/53	disease causing

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

Other links and lift over

dbSNP: rs587777300; hg19: chr5-138643448;