5-139322772-T-G

Variant names:

• chr5-139322772-T-G
• rs770765421
• NM_018834.6:c.1953T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The ENST00000394805.8(MATR3):​c.1953T>G​(p.Leu651Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,864 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 Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. L651L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MATR3 ENST00000394805.8 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.187
• 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):

• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-139322772-T-G is Benign according to our data. Variant chr5-139322772-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3357348.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.187 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394805.8. 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.1953T>G	p.Leu651Leu	synonymous	Exon 12 of 15	NP_061322.2
	MATR3	NM_001400441.1		c.1953T>G	p.Leu651Leu	synonymous	Exon 13 of 16	NP_001387370.1
	MATR3	NM_001400442.1		c.1953T>G	p.Leu651Leu	synonymous	Exon 15 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.1953T>G	p.Leu651Leu	synonymous	Exon 12 of 15	ENSP00000378284.3
	MATR3	ENST00000502929.5	TSL:2	c.1953T>G	p.Leu651Leu	synonymous	Exon 17 of 20	ENSP00000422319.1
	MATR3	ENST00000618441.5	TSL:1	c.1953T>G	p.Leu651Leu	synonymous	Exon 12 of 15	ENSP00000482895.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727230

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: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112004

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

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	MATR3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.6
DANN	Benign	0.58
PhyloP100		-0.19
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs770765421; hg19: chr5-138658461;