11-102778751-T-C

Position:

chr11-102778751-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 3P and 8B. PVS1_ModeratePP3BS1BS2

The NM_002425.3(MMP10):c.497-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.0176 in 1,613,542 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.013 ( 19 hom., cov: 32)

Exomes 𝑓: 0.018 ( 297 hom. )

Consequence

MMP10
NM_002425.3 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

MMP10 (HGNC:7156): (matrix metallopeptidase 10) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this family are involved in the breakdown of extracellular matrix in normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down fibronectin, laminin, elastin, proteoglycan core protein, gelatins, and several types of collagen. The gene is part of a cluster of MMP genes on chromosome 11. [provided by RefSeq, Jan 2016]

MMP10 links:

WTAPP1 (HGNC:44115): (WTAP pseudogene 1)

WTAPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0873515 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.1, offset of 33, new splice context is: ttactcttttgatggcccAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

PP3

Multiple lines of computational evidence support a deleterious effect 5: Cadd, dbscSNV1_ADA, dbscSNV1_RF, max_spliceai, Eigen [when BayesDel_addAF, Dann, MutationTaster was below the threshold]

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.013 (1978/152368) while in subpopulation NFE AF= 0.0197 (1337/68038). AF 95% confidence interval is 0.0188. There are 19 homozygotes in gnomad4. There are 908 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP10	NM_002425.3 linkuse as main transcript	c.497-2A>G		splice_acceptor_variant		ENST00000279441.9	NP_002416.1

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	Appris
MMP10	ENST00000279441.9 linkuse as main transcript	c.497-2A>G	splice_acceptor_variant	1	NM_002425.3	ENSP00000279441	P1
WTAPP1	ENST00000371455.7 linkuse as main transcript	n.325-19273T>C	intron_variant, non_coding_transcript_variant	4
MMP10	ENST00000539681.1 linkuse as main transcript	c.497-35A>G	intron_variant	3		ENSP00000441485

Frequencies

GnomAD3 genomes

AF:

0.0130

AC:

1977

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00379

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0179

Gnomad ASJ

AF:

0.0193

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0155

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0136

AC:

3394

AN:

250442

Hom.:

AF XY:

0.0139

AC XY:

1888

AN XY:

135376

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.0122

Gnomad ASJ exome

AF:

0.0197

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0154

Gnomad FIN exome

AF:

0.00384

Gnomad NFE exome

AF:

0.0181

Gnomad OTH exome

AF:

0.0168

GnomAD4 exome

AF:

0.0181

AC:

26495

AN:

1461174

Hom.:

297

Cov.:

AF XY:

0.0181

AC XY:

13129

AN XY:

726870

show subpopulations

Gnomad4 AFR exome

AF:

0.00344

Gnomad4 AMR exome

AF:

0.0128

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0165

Gnomad4 FIN exome

AF:

0.00384

Gnomad4 NFE exome

AF:

0.0203

Gnomad4 OTH exome

AF:

0.0171

GnomAD4 genome

AF:

0.0130

AC:

1978

AN:

152368

Hom.:

Cov.:

AF XY:

0.0122

AC XY:

908

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00378

Gnomad4 AMR

AF:

0.0178

Gnomad4 ASJ

AF:

0.0193

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0175

Hom.:

Bravo

AF:

0.0126

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0241

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0201

AC:

173

ExAC

AF:

0.0135

AC:

1634

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

MMP10: BS1, BS2; WTAPP1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

GERP RS

3.3

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.92

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.48

Position offset: -35

DS_AL_spliceai

1.0

Position offset: -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