rs779413744

chr2-20006016-G-Achr2-20006016-G-Cchr2-20006016-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM5 BP4_Moderate BP6_Moderate

The NM_002381.5(MATN3):c.518C>T(p.Ala173Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A173D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MATN3 NM_002381.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.210

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM1: In a domain VWFA (size 175) in uniprot entity MATN3_HUMAN there are 35 pathogenic changes around while only 7 benign (83%) in NM_002381.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-20006016-G-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.17486206).
• BP6: Variant 2-20006016-G-A is Benign according to our data. Variant chr2-20006016-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2411438.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MATN3	NM_002381.5	c.518C>T	p.Ala173Val	missense_variant	2/8	ENST00000407540.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MATN3	ENST00000407540.8	c.518C>T	p.Ala173Val	missense_variant	2/8	1	NM_002381.5	P1
MATN3	ENST00000421259.2	c.518C>T	p.Ala173Val	missense_variant	2/7	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000401 AC: 10 AN: 249252 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135220

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461704 Hom.: 0 Cov.: 61 AF XY: 0.00000963 AC XY: 7 AN XY: 727134

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	6.8
Dann	Benign	0.95
DEOGEN2	Benign	0.38	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.21
Sift	Benign	0.11	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.10	B;.
Vest4		0.17
MutPred		0.75		Loss of disorder (P = 0.0877);Loss of disorder (P = 0.0877);
MVP		0.65
MPC		0.20
ClinPred		0.046	T
GERP RS		-4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.70

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: rs779413744; hg19: chr2-20205777;