rs192397681

Variant names:

• chr5-139307374-T-A
• rs192397681
• NM_018834.6:c.-42T>A

Your query was ambiguous. Multiple possible variants found:

• chr5-139307374-T-A
• chr5-139307374-T-C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_018834.6(MATR3):​c.-42T>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000562 in 1,440,590 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (4 hom.)
• Consequence: MATR3 NM_018834.6 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.76
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 5-139307374-T-A is Benign according to our data. Variant chr5-139307374-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1301101.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 38 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.-42T>A		5_prime_UTR	Exon 2 of 15	NP_061322.2
	MATR3	NM_001400441.1		c.-42T>A		5_prime_UTR	Exon 3 of 16	NP_001387370.1	A8MXP9
	MATR3	NM_001400442.1		c.-42T>A		5_prime_UTR	Exon 5 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.-42T>A		5_prime_UTR	Exon 2 of 15	ENSP00000378284.3	P43243-1
	MATR3	ENST00000502929.5	TSL:2	c.-42T>A		5_prime_UTR	Exon 7 of 20	ENSP00000422319.1	A8MXP9
	MATR3	ENST00000618441.5	TSL:1	c.-42T>A		5_prime_UTR	Exon 2 of 15	ENSP00000482895.1	P43243-1

Frequencies

GnomAD3 genomes AF: 0.000251 AC: 38 AN: 151370 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000310

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000585 AC: 107 AN: 182854 AF XY: 0.000576

Gnomad AFR exome AF: 0.0000899

Gnomad AMR exome AF: 0.000838

Gnomad ASJ exome AF: 0.000291

Gnomad EAS exome AF: 0.000819

Gnomad FIN exome AF: 0.000565

Gnomad NFE exome AF: 0.000463

Gnomad OTH exome AF: 0.000467

GnomAD4 exome AF: 0.000599 AC: 772 AN: 1289104 Hom.: 4 Cov.: 33 AF XY: 0.000598 AC XY: 383 AN XY: 640138

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

African (AFR) AF: 0.000134 AC: 4 AN: 29946

American (AMR) AF: 0.00113 AC: 36 AN: 31992

Ashkenazi Jewish (ASJ) AF: 0.000224 AC: 5 AN: 22344

East Asian (EAS) AF: 0.000653 AC: 25 AN: 38264

South Asian (SAS) AF: 0.00117 AC: 83 AN: 70988

European-Finnish (FIN) AF: 0.000331 AC: 16 AN: 48288

Middle Eastern (MID) AF: 0.000600 AC: 3 AN: 5002

European-Non Finnish (NFE) AF: 0.000582 AC: 575 AN: 988340

Other (OTH) AF: 0.000463 AC: 25 AN: 53940

⚠️ 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: 0.000251 AC: 38 AN: 151486 Hom.: 0 Cov.: 32 AF XY: 0.000230 AC XY: 17 AN XY: 74016

African (AFR) AF: 0.0000969 AC: 4 AN: 41280

American (AMR) AF: 0.000132 AC: 2 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00193 AC: 10 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.0000958 AC: 1 AN: 10440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000310 AC: 21 AN: 67842

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00235 Hom.: 1

Asia WGS AF: 0.00115 AC: 4 AN: 3476

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
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.011
DANN	Benign	0.60
PhyloP100		-4.8
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: rs192397681; hg19: chr5-138643063; COSMIC: COSV63079148; COSMIC: COSV63079148;