NM_002381.5:c.1406-4C>T

Variant names:

• chr2-19993170-G-A
• rs35973216
• NM_002381.5:c.1406-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002381.5(MATN3):​c.1406-4C>T variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.0001580
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.331
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002381.5. 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
	MATN3	NM_002381.5	MANE Select	c.1406-4C>T		splice_region intron	N/A	NP_002372.1	O15232-1
	WDR35-DT	NR_110235.1		n.291+2676G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MATN3	ENST00000407540.8	TSL:1 MANE Select	c.1406-4C>T		splice_region intron	N/A	ENSP00000383894.3	O15232-1
	MATN3	ENST00000421259.2	TSL:1	c.1280-4C>T		splice_region intron	N/A	ENSP00000398753.2	O15232-2
	MATN3	ENST00000856777.1		c.1400-4C>T		splice_region intron	N/A	ENSP00000526836.1

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38395 AN: 151846 Hom.: 4914 Cov.: 33

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

GnomAD2 exomes AF: 0.251 AC: 61569 AN: 245432 AF XY: 0.247

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 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.: 29 AF XY: 0.249 AC XY: 179171 AN XY: 720676

African (AFR) AF: 0.255 AC: 8472 AN: 33166

American (AMR) AF: 0.282 AC: 12550 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 6861 AN: 26020

East Asian (EAS) AF: 0.273 AC: 10791 AN: 39536

South Asian (SAS) AF: 0.205 AC: 17599 AN: 85748

European-Finnish (FIN) AF: 0.271 AC: 14380 AN: 53154

Middle Eastern (MID) AF: 0.214 AC: 1222 AN: 5710

European-Non Finnish (NFE) AF: 0.251 AC: 275649 AN: 1099678

Other (OTH) AF: 0.246 AC: 14692 AN: 59832

GnomAD4 genome AF: 0.253 AC: 38429 AN: 151964 Hom.: 4921 Cov.: 33 AF XY: 0.253 AC XY: 18800 AN XY: 74250

African (AFR) AF: 0.255 AC: 10574 AN: 41460

American (AMR) AF: 0.254 AC: 3875 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 878 AN: 3466

East Asian (EAS) AF: 0.232 AC: 1202 AN: 5172

South Asian (SAS) AF: 0.207 AC: 1000 AN: 4826

European-Finnish (FIN) AF: 0.271 AC: 2852 AN: 10508

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.252 AC: 17134 AN: 67956

Other (OTH) AF: 0.255 AC: 539 AN: 2114

Alfa AF: 0.253 Hom.: 2564

Bravo AF: 0.253

Asia WGS AF: 0.211 AC: 735 AN: 3476

EpiCase AF: 0.242

EpiControl AF: 0.242

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cranioectodermal dysplasia (1)
-	-	1	Multiple epiphyseal dysplasia type 5 (1)
-	-	1	Multiple Epiphyseal Dysplasia, Dominant (1)
-	-	1	not specified (1)
-	-	1	Short rib-polydactyly syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.0
DANN	Benign	0.70
PhyloP100		0.33
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35973216; hg19: chr2-20192931; COSMIC: COSV55603207; COSMIC: COSV55603207;