5-139293986-A-T

Variant names:

• chr5-139293986-A-T
• rs772859892
• ENST00000618441.5:c.-220A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001400445.1(MATR3):​c.-1189A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000892 in 1,121,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.9e-7 (0 hom.)
• Consequence: MATR3 NM_001400445.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.37740102).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001400445.1. 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+181A>T		intron	N/A	NP_061322.2
	MATR3	NM_001400445.1		c.-1189A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001387374.1	A8MXP9
	MATR3	NM_001194955.2		c.-220A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001181884.1	A0A0R4J2E8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATR3	ENST00000618441.5	TSL:1	c.-220A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000482895.1	P43243-1
	MATR3	ENST00000618441.5	TSL:1	c.-220A>T		5_prime_UTR	Exon 1 of 15	ENSP00000482895.1	P43243-1
	MATR3	ENST00000394805.8	TSL:1 MANE Select	c.-178+181A>T		intron	N/A	ENSP00000378284.3	P43243-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.92e-7 AC: 1 AN: 1121378 Hom.: 0 Cov.: 30 AF XY: 0.00000186 AC XY: 1 AN XY: 536400

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

African (AFR) AF: 0.00 AC: 0 AN: 23502

American (AMR) AF: 0.00 AC: 0 AN: 11208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16498

East Asian (EAS) AF: 0.00 AC: 0 AN: 26684

South Asian (SAS) AF: 0.00 AC: 0 AN: 33692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3894

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 937530

Other (OTH) AF: 0.00 AC: 0 AN: 45244

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Benign	0.10
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.98	T
PhyloP100		1.5
PROVEAN	Benign	1.4	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Vest4		0.46
MutPred		0.26		Gain of solvent accessibility (P = 0.0917)
MVP		0.75
ClinPred		0.95	D
GERP RS		3.9
PromoterAI		-0.011	Neutral
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs772859892; hg19: chr5-138629675;