5-139330103-T-C

Position:

• chr5-139330103-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_018834.6(MATR3):​c.*708T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.034 in 454,522 control chromosomes in the GnomAD database, including 352 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (115 hom., cov: 33)
  • Exomes 𝑓: 0.034 (237 hom.)
• Consequence: MATR3 NM_018834.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.24

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 5-139330103-T-C is Benign according to our data. Variant chr5-139330103-T-C is described in ClinVar as [Benign]. Clinvar id is 351159.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0333 (5070/152310) while in subpopulation NFE AF= 0.0479 (3258/68018). AF 95% confidence interval is 0.0465. There are 115 homozygotes in gnomad4. There are 2533 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 5070 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATR3	NM_018834.6	c.*708T>C		3_prime_UTR_variant	15/15	ENST00000394805.8	NP_061322.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MATR3	ENST00000394805.8	c.*708T>C		3_prime_UTR_variant	15/15	1	NM_018834.6	ENSP00000378284.3
MATR3	ENST00000394800.6	c.*708T>C		3_prime_UTR_variant	19/19	5		ENSP00000378279.2
MATR3	ENST00000502929.5	c.*708T>C		3_prime_UTR_variant	20/20	2		ENSP00000422319.1

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5074 AN: 152192 Hom.: 115 Cov.: 33

Gnomad AFR AF: 0.00811

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00806

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0479

Gnomad OTH AF: 0.0339

GnomAD3 exomes AF: 0.0319 AC: 4355 AN: 136562 Hom.: 95 AF XY: 0.0313 AC XY: 2320 AN XY: 74146

Gnomad AFR exome AF: 0.00730

Gnomad AMR exome AF: 0.0315

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.000190

Gnomad SAS exome AF: 0.00840

Gnomad FIN exome AF: 0.0624

Gnomad NFE exome AF: 0.0502

Gnomad OTH exome AF: 0.0384

GnomAD4 exome AF: 0.0344 AC: 10385 AN: 302212 Hom.: 237 Cov.: 0 AF XY: 0.0321 AC XY: 5522 AN XY: 172244

Gnomad4 AFR exome AF: 0.00865

Gnomad4 AMR exome AF: 0.0313

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.000217

Gnomad4 SAS exome AF: 0.00979

Gnomad4 FIN exome AF: 0.0538

Gnomad4 NFE exome AF: 0.0472

Gnomad4 OTH exome AF: 0.0380

GnomAD4 genome AF: 0.0333 AC: 5070 AN: 152310 Hom.: 115 Cov.: 33 AF XY: 0.0340 AC XY: 2533 AN XY: 74480

Gnomad4 AFR AF: 0.00808

Gnomad4 AMR AF: 0.0418

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00786

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0479

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0354 Hom.: 33

Bravo AF: 0.0324

Asia WGS AF: 0.00577 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 21 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs14109; hg19: chr5-138665792;