2-19992935-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002381.5(MATN3):c.*176C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 600,112 control chromosomes in the GnomAD database, including 64,608 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16011 hom., cov: 33)
  • Exomes 𝑓: 0.46 (48597 hom.)
• Consequence: MATN3 NM_002381.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.515

Genes affected

MATN3 (HGNC:6909): (matrilin 3) This gene encodes a member of von Willebrand factor A domain containing protein family. This family of proteins is thought to be involved in the formation of filamentous networks in the extracellular matrices of various tissues. This protein contains two von Willebrand factor A domains; it is present in the cartilage extracellular matrix and has a role in the development and homeostasis of cartilage and bone. Mutations in this gene result in multiple epiphyseal dysplasia. [provided by RefSeq, Jul 2008]

WDR35-DT (HGNC:55818): (WDR35 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-19992935-G-A is Benign according to our data. Variant chr2-19992935-G-A is described in ClinVar as [Benign]. Clinvar id is 333410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.62 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN3	NM_002381.5	c.*176C>T		3_prime_UTR_variant	8/8	ENST00000407540.8
WDR35-DT	NR_110235.1	n.291+2441G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN3	ENST00000407540.8	c.*176C>T		3_prime_UTR_variant	8/8	1	NM_002381.5	P1
WDR35-DT	ENST00000416575.2	n.284+2441G>A		intron_variant, non_coding_transcript_variant		2
WDR35-DT	ENST00000658200.1	n.286+2441G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69222 AN: 151848 Hom.: 15988 Cov.: 33

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.531

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.639

Gnomad SAS AF: 0.590

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.465

GnomAD4 exome AF: 0.457 AC: 204786 AN: 448146 Hom.: 48597 Cov.: 5 AF XY: 0.463 AC XY: 110420 AN XY: 238608

Gnomad4 AFR exome AF: 0.456

Gnomad4 AMR exome AF: 0.462

Gnomad4 ASJ exome AF: 0.411

Gnomad4 EAS exome AF: 0.713

Gnomad4 SAS exome AF: 0.580

Gnomad4 FIN exome AF: 0.422

Gnomad4 NFE exome AF: 0.420

Gnomad4 OTH exome AF: 0.438

GnomAD4 genome AF: 0.456 AC: 69296 AN: 151966 Hom.: 16011 Cov.: 33 AF XY: 0.461 AC XY: 34254 AN XY: 74278

Gnomad4 AFR AF: 0.468

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.409

Gnomad4 EAS AF: 0.639

Gnomad4 SAS AF: 0.588

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.422

Gnomad4 OTH AF: 0.472

Alfa AF: 0.433 Hom.: 3201

Bravo AF: 0.456

Asia WGS AF: 0.621 AC: 2158 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cranioectodermal dysplasia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Multiple Epiphyseal Dysplasia, Dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multiple epiphyseal dysplasia type 5 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. -

Short rib-polydactyly syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.9
Dann	Benign	0.29

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

Publications

LitVar

Other links and lift over

dbSNP: rs7569975; hg19: chr2-20192696; COSMIC: COSV55604478; COSMIC: COSV55604478;