5-139294034-C-CAA

Variant names:

• chr5-139294034-C-CAA
• NM_018834.6:c.-178+229_-178+230insAA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001194955.2(MATR3):​c.-178+6_-178+7insAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.00055 (5 hom.)
  • Failed GnomAD Quality Control
• Consequence: MATR3 NM_001194955.2 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.328
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-139294034-C-CAA is Benign according to our data. Variant chr5-139294034-C-CAA is described in ClinVar as Likely_benign. ClinVar VariationId is 3352357.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001194955.2. 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.-178+229_-178+230insAA		intron	N/A	NP_061322.2
	MATR3	NM_001400445.1		c.-1141_-1140insAA		5_prime_UTR	Exon 1 of 15	NP_001387374.1	A8MXP9
	MATR3	NM_001400457.1		c.-760_-759insAA		5_prime_UTR	Exon 1 of 15	NP_001387386.1	A0A0R4J2E8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATR3	ENST00000394805.8	TSL:1 MANE Select	c.-178+229_-178+230insAA		intron	N/A	ENSP00000378284.3	P43243-1
	MATR3	ENST00000502929.5	TSL:2	c.-178+459_-178+460insAA		intron	N/A	ENSP00000422319.1	A8MXP9
	MATR3	ENST00000618441.5	TSL:1	c.-178+6_-178+7insAA		splice_region intron	N/A	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000551 AC: 604 AN: 1095422 Hom.: 5 Cov.: 30 AF XY: 0.000753 AC XY: 395 AN XY: 524420

African (AFR) AF: 0.000255 AC: 6 AN: 23516

American (AMR) AF: 0.00813 AC: 90 AN: 11064

Ashkenazi Jewish (ASJ) AF: 0.00588 AC: 90 AN: 15308

East Asian (EAS) AF: 0.00 AC: 0 AN: 26768

South Asian (SAS) AF: 0.00456 AC: 151 AN: 33150

European-Finnish (FIN) AF: 0.000472 AC: 11 AN: 23320

Middle Eastern (MID) AF: 0.00101 AC: 4 AN: 3980

European-Non Finnish (NFE) AF: 0.000237 AC: 217 AN: 913894

Other (OTH) AF: 0.000788 AC: 35 AN: 44422

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr5-138629723;