rs137955225

chr10-125770368-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_147191.1(MMP21):c.1203G>A(p.Trp401Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000187 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: MMP21 NM_147191.1 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.33

Genes affected

MMP21 (HGNC:14357): (matrix metallopeptidase 21) This gene encodes a member of the matrix metalloproteinase family. Proteins in this family are involved in the breakdown of extracellular matrix for both normal physiological processes, such as embryonic development, reproduction, and tissue remodeling, and disease processes, such as asthma and tumor metastasis. The encoded protein may play an important role in embryogenesis, particularly in neuronal cells, as well as in lymphocyte development and survival. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-125770368-C-T is Pathogenic according to our data. Variant chr10-125770368-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 289001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-125770368-C-T is described in Lovd as [Pathogenic]. Variant chr10-125770368-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP21	NM_147191.1	c.1203G>A	p.Trp401Ter	stop_gained	5/7	ENST00000368808.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP21	ENST00000368808.3	c.1203G>A	p.Trp401Ter	stop_gained	5/7	1	NM_147191.1	P1
MMP21	ENST00000651977.1	c.474G>A	p.Trp158Ter	stop_gained	2/4
MMP21	ENST00000652044.1	c.225G>A	p.Trp75Ter	stop_gained	1/2
MMP21	ENST00000651834.1	c.*152G>A		3_prime_UTR_variant, NMD_transcript_variant	3/5

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251480 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

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: 0.000123

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.000176 AC XY: 128 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000291

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: 0.000216

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74460

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000242

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Visceral heterotaxy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2018

The p.Trp401X (NM_147191.1 c.1203G>A) variant in MMP21 has been previously repor ted in compound heterozygous dizygotic twins with heterotaxy (Guimier 2015). It has also been reported in ClinVar (Variation ID#289001). This variant has been i dentified in 0.035% (12/34418) of Latino chromosomes by the Genome Aggregation D atabase (http://gnomad.broadinstitute.org; rs137955225). Although this variant h as been seen in the general population, its frequency is low enough to be consis tent with a recessive carrier frequency. This nonsense variant leads to a premat ure termination codon at position 401, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the MMP21 gene has been associ ated with heterotaxy. In summary, although additional studies are required to fu lly establish its clinical significance, the p.Trp401X variant is likely pathoge nic for heterotaxy in an autosomal recessive manner based on its occurrence in a ffected individuals and predicted impact on the protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 10, 2018

- -

Heterotaxy, visceral, 7, autosomal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	39
Dann	Uncertain	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	A
Vest4		0.25
GERP RS		5.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137955225; hg19: chr10-127458937;