Genetic Variant MMP8:p.Tyr388His (chr11-102714584-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002424.3(MMP8):c.1162T>C(p.Tyr388His) variant causes a missense change. The variant allele was found at a frequency of 0.00000445 in 1,348,158 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: 31)

Exomes 𝑓: 0.0000045 ( 0 hom. )

Consequence

MMP8
NM_002424.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.83

Variant links:

Genes affected

MMP8 (HGNC:7175): (matrix metallopeptidase 8) This gene encodes a member of the matrix metalloproteinase (MMP) family of proteins. These proteins are involved in the breakdown of extracellular matrix in embryonic development, reproduction, and tissue remodeling, as well as in disease processes, such as arthritis and metastasis. Proteolysis at different sites on this protein results in multiple active forms of the enzyme with distinct N-termini. This protein functions in the degradation of type I, II and III collagens. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

MMP8 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMP8	NM_002424.3 link	c.1162T>C	p.Tyr388His	missense_variant	Exon 8 of 10	ENST00000236826.8	NP_002415.1	P22894

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MMP8	ENST00000236826.8 link	c.1162T>C	p.Tyr388His	missense_variant	Exon 8 of 10	1	NM_002424.3	ENSP00000236826.3	P22894
MMP8	ENST00000438475.2 link	c.961+720T>C		intron_variant	Intron 7 of 8	5		ENSP00000401004.2	H7C1M3
MMP8	ENST00000528662.6 link	n.*1139T>C		non_coding_transcript_exon_variant	Exon 10 of 12	5		ENSP00000431431.2	E9PL87
MMP8	ENST00000528662.6 link	n.*1139T>C		3_prime_UTR_variant	Exon 10 of 12	5		ENSP00000431431.2	E9PL87

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

180214

Hom.:

AF XY:

0.0000201

AC XY:

AN XY:

99260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000968

Gnomad SAS exome

AF:

0.0000516

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000111

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000445

AC:

AN:

1348158

Hom.:

Cov.:

AF XY:

0.00000299

AC XY:

AN XY:

668876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000303

Gnomad4 SAS exome

AF:

0.0000147

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1162T>C (p.Y388H) alteration is located in exon 8 (coding exon 8) of the MMP8 gene. This alteration results from a T to C substitution at nucleotide position 1162, causing the tyrosine (Y) at amino acid position 388 to be replaced by a histidine (H). 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

Uncertain

0.44

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.84

M_CAP

Benign

0.013

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.82

MutationAssessor

Pathogenic

3.5

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.26

Sift

Uncertain

0.0070

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.56

MutPred

0.78

Loss of stability (P = 0.0776);

MVP

0.59

MPC

0.31

ClinPred

0.95

GERP RS

5.5

Varity_R

0.39

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

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

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