NM_018834.6:c.-177-90dupT

Variant names:

• chr5-139307139-G-GT
• rs796858947
• NM_018834.6:c.-177-90dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_018834.6(MATR3):​c.-177-90dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 780,898 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (1 hom.)
• Consequence: MATR3 NM_018834.6 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.379
• 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.

• BP6: Variant 5-139307139-G-GT is Benign according to our data. Variant chr5-139307139-G-GT is described in ClinVar as Likely_benign. ClinVar VariationId is 1212470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 495 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.-177-90dupT		intron	N/A	NP_061322.2
	MATR3	NM_001400441.1		c.-177-90dupT		intron	N/A	NP_001387370.1	A8MXP9
	MATR3	NM_001400442.1		c.-177-90dupT		intron	N/A	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.-177-90dupT		intron	N/A	ENSP00000378284.3	P43243-1
	MATR3	ENST00000502929.5	TSL:2	c.-177-90dupT		intron	N/A	ENSP00000422319.1	A8MXP9
	MATR3	ENST00000618441.5	TSL:1	c.-177-90dupT		intron	N/A	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes AF: 0.00335 AC: 493 AN: 147266 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00191

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000790

Gnomad SAS AF: 0.00215

Gnomad FIN AF: 0.000208

Gnomad MID AF: 0.00974

Gnomad NFE AF: 0.000285

Gnomad OTH AF: 0.00297

GnomAD4 exome AF: 0.00843 AC: 5341 AN: 633528 Hom.: 1 AF XY: 0.00851 AC XY: 2587 AN XY: 303862

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0186 AC: 244 AN: 13098

American (AMR) AF: 0.0101 AC: 58 AN: 5720

Ashkenazi Jewish (ASJ) AF: 0.00880 AC: 68 AN: 7728

East Asian (EAS) AF: 0.00915 AC: 100 AN: 10930

South Asian (SAS) AF: 0.0101 AC: 178 AN: 17560

European-Finnish (FIN) AF: 0.00859 AC: 57 AN: 6638

Middle Eastern (MID) AF: 0.0123 AC: 20 AN: 1624

European-Non Finnish (NFE) AF: 0.00805 AC: 4393 AN: 545440

Other (OTH) AF: 0.00900 AC: 223 AN: 24790

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00336 AC: 495 AN: 147370 Hom.: 1 Cov.: 32 AF XY: 0.00323 AC XY: 232 AN XY: 71774

African (AFR) AF: 0.0105 AC: 424 AN: 40210

American (AMR) AF: 0.00190 AC: 28 AN: 14710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.000791 AC: 4 AN: 5054

South Asian (SAS) AF: 0.00194 AC: 9 AN: 4642

European-Finnish (FIN) AF: 0.000208 AC: 2 AN: 9596

Middle Eastern (MID) AF: 0.0105 AC: 3 AN: 286

European-Non Finnish (NFE) AF: 0.000285 AC: 19 AN: 66554

Other (OTH) AF: 0.00294 AC: 6 AN: 2038

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.38
Mutation Taster		=100/0	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: rs796858947; hg19: chr5-138642828;