chr5-139319497-G-A

Variant names:

• chr5-139319497-G-A
• rs1033118784
• NM_018834.6:c.1598G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_018834.6(MATR3):​c.1598G>A​(p.Ser533Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000219 in 1,460,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.14
• Publications: 0 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):

• distal myopathy with vocal cord weakness

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• amyotrophic lateral sclerosis type 21

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18239191).
• BS2: High AC in GnomAdExome4 at 32 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATR3	NM_018834.6	MANE Select	c.1598G>A	p.Ser533Asn	missense	Exon 9 of 15	NP_061322.2
	MATR3	NM_001400441.1		c.1598G>A	p.Ser533Asn	missense	Exon 10 of 16	NP_001387370.1	A8MXP9
	MATR3	NM_001400442.1		c.1598G>A	p.Ser533Asn	missense	Exon 12 of 18	NP_001387371.1	A8MXP9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATR3	ENST00000394805.8	TSL:1 MANE Select	c.1598G>A	p.Ser533Asn	missense	Exon 9 of 15	ENSP00000378284.3	P43243-1
	MATR3	ENST00000502929.5	TSL:2	c.1598G>A	p.Ser533Asn	missense	Exon 14 of 20	ENSP00000422319.1	A8MXP9
	MATR3	ENST00000618441.5	TSL:1	c.1598G>A	p.Ser533Asn	missense	Exon 9 of 15	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1460226 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 726516

African (AFR) AF: 0.00 AC: 0 AN: 33442

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5374

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111026

Other (OTH) AF: 0.0000166 AC: 1 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 21 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.037	T
Eigen	Benign	0.0097
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
PhyloP100		5.1
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.43	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.025	B
Vest4		0.38
MutPred		0.48		Loss of sheet (P = 0.0457)
MVP		0.74
MPC		2.0
ClinPred		0.87	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.71
Mutation Taster		=80/20	polymorphism

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: rs1033118784; hg19: chr5-138655186;