11-102693972-A-G

Position:

• chr11-102693972-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The ENST00000260229.5(MMP27):​c.1127T>C​(p.Ile376Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000048 in 1,459,828 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MMP27 ENST00000260229.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.93

Genes affected

MMP27 (HGNC:14250): (matrix metallopeptidase 27) Proteins of the matrix metalloproteinase (MMP) 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. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP27	NM_022122.3	c.1127T>C	p.Ile376Thr	missense_variant	8/10	ENST00000260229.5	NP_071405.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP27	ENST00000260229.5	c.1127T>C	p.Ile376Thr	missense_variant	8/10	1	NM_022122.3	ENSP00000260229.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1459828 Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5 AN XY: 726192

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.1127T>C (p.I376T) alteration is located in exon 8 (coding exon 8) of the MMP27 gene. This alteration results from a T to C substitution at nucleotide position 1127, causing the isoleucine (I) at amino acid position 376 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.018	T
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.90	T
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.89		Gain of disorder (P = 0.0276);
MVP		0.77
MPC		0.24
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-102564703;