5-139322767-A-C

Variant names:

• chr5-139322767-A-C
• rs749026971
• NM_018834.6:c.1948A>C

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.1948A>C​(p.Met650Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M650V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: MATR3 NM_018834.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54
• 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 (REVEL=0.11).
• BS2: High AC in GnomAdExome4 at 34 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.1948A>C	p.Met650Leu	missense	Exon 12 of 15	NP_061322.2
	MATR3	NM_001400441.1		c.1948A>C	p.Met650Leu	missense	Exon 13 of 16	NP_001387370.1	A8MXP9
	MATR3	NM_001400442.1		c.1948A>C	p.Met650Leu	missense	Exon 15 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.1948A>C	p.Met650Leu	missense	Exon 12 of 15	ENSP00000378284.3	P43243-1
	MATR3	ENST00000502929.5	TSL:2	c.1948A>C	p.Met650Leu	missense	Exon 17 of 20	ENSP00000422319.1	A8MXP9
	MATR3	ENST00000618441.5	TSL:1	c.1948A>C	p.Met650Leu	missense	Exon 12 of 15	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251438 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000233 AC: 34 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000297 AC: 33 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.71
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Benign	0.0017	T
PhyloP100		1.5
ClinPred		0.079	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.092
Mutation Taster		=97/3	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: rs749026971; hg19: chr5-138658456;