chr2-19993170-G-A

Position:

chr2-19993170-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002381.5(MATN3):c.1406-4C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,599,264 control chromosomes in the GnomAD database, including 51,216 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.25 ( 4921 hom., cov: 33)

Exomes 𝑓: 0.25 ( 46295 hom. )

Consequence

MATN3
NM_002381.5 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001580

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.331

Variant links:

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]

MATN3 links:

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

WDR35-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BP6

Variant 2-19993170-G-A is Benign according to our data. Variant chr2-19993170-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 258647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.251 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MATN3	NM_002381.5 linkuse as main transcript	c.1406-4C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000407540.8	NP_002372.1
WDR35-DT	NR_110235.1 linkuse as main transcript	n.291+2676G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris	UniProt
MATN3	ENST00000407540.8 linkuse as main transcript	c.1406-4C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_002381.5	ENSP00000383894	P1	O15232-1
MATN3	ENST00000421259.2 linkuse as main transcript	c.1280-4C>T	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		ENSP00000398753		O15232-2
WDR35-DT	ENST00000416575.2 linkuse as main transcript	n.284+2676G>A	intron_variant, non_coding_transcript_variant	2
WDR35-DT	ENST00000658200.1 linkuse as main transcript	n.286+2676G>A	intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.253

AC:

38395

AN:

151846

Hom.:

4914

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.361

Gnomad AMR

AF:

0.254

Gnomad ASJ

AF:

0.253

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.208

Gnomad FIN

AF:

0.271

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.252

Gnomad OTH

AF:

0.250

GnomAD3 exomes

AF:

0.251

AC:

61569

AN:

245432

Hom.:

7868

AF XY:

0.247

AC XY:

32938

AN XY:

133434

show subpopulations

Gnomad AFR exome

AF:

0.246

Gnomad AMR exome

AF:

0.289

Gnomad ASJ exome

AF:

0.262

Gnomad EAS exome

AF:

0.216

Gnomad SAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.273

Gnomad NFE exome

AF:

0.252

Gnomad OTH exome

AF:

0.256

GnomAD4 exome

AF:

0.250

AC:

362216

AN:

1447300

Hom.:

46295

Cov.:

AF XY:

0.249

AC XY:

179171

AN XY:

720676

show subpopulations

Gnomad4 AFR exome

AF:

0.255

Gnomad4 AMR exome

AF:

0.282

Gnomad4 ASJ exome

AF:

0.264

Gnomad4 EAS exome

AF:

0.273

Gnomad4 SAS exome

AF:

0.205

Gnomad4 FIN exome

AF:

0.271

Gnomad4 NFE exome

AF:

0.251

Gnomad4 OTH exome

AF:

0.246

GnomAD4 genome

AF:

0.253

AC:

38429

AN:

151964

Hom.:

4921

Cov.:

AF XY:

0.253

AC XY:

18800

AN XY:

74250

show subpopulations

Gnomad4 AFR

AF:

0.255

Gnomad4 AMR

AF:

0.254

Gnomad4 ASJ

AF:

0.253

Gnomad4 EAS

AF:

0.232

Gnomad4 SAS

AF:

0.207

Gnomad4 FIN

AF:

0.271

Gnomad4 NFE

AF:

0.252

Gnomad4 OTH

AF:

0.255

Alfa

AF:

0.254

Hom.:

2421

Bravo

AF:

0.253

Asia WGS

AF:

0.211

AC:

735

AN:

3476

EpiCase

AF:

0.242

EpiControl

AF:

0.242

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Cranioectodermal dysplasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Multiple Epiphyseal Dysplasia, Dominant

Benign:1

Likely 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 12, 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

-0.77

CADD

Benign

8.0

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over