14-22836827-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_004995.4(MMP14):c.10G>A(p.Ala4Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,603,280 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0087 (24 hom., cov: 31)
  • Exomes 𝑓: 0.00095 (19 hom.)
• Consequence: MMP14 NM_004995.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.154

Genes affected

MMP14 (HGNC:7160): (matrix metallopeptidase 14) 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. However, the protein encoded by this gene is a member of the membrane-type MMP (MT-MMP) subfamily; each member of this subfamily contains a potential transmembrane domain suggesting that these proteins are expressed at the cell surface rather than secreted. This protein activates MMP2 protein, and this activity may be involved in tumor invasion. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028084815).
• BP6: Variant 14-22836827-G-A is Benign according to our data. Variant chr14-22836827-G-A is described in ClinVar as [Benign]. Clinvar id is 776819.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00873 (1327/152068) while in subpopulation AFR AF= 0.0305 (1267/41490). AF 95% confidence interval is 0.0291. There are 24 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMP14	NM_004995.4	c.10G>A	p.Ala4Thr	missense_variant	1/10	ENST00000311852.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMP14	ENST00000311852.11	c.10G>A	p.Ala4Thr	missense_variant	1/10	1	NM_004995.4	P1

Frequencies

GnomAD3 genomes AF: 0.00874 AC: 1328 AN: 151952 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00432

GnomAD3 exomes AF: 0.00239 AC: 576 AN: 240564 Hom.: 6 AF XY: 0.00168 AC XY: 220 AN XY: 130774

Gnomad AFR exome AF: 0.0324

Gnomad AMR exome AF: 0.00157

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: 0.000140

Gnomad OTH exome AF: 0.00136

GnomAD4 exome AF: 0.000952 AC: 1382 AN: 1451212 Hom.: 19 Cov.: 28 AF XY: 0.000803 AC XY: 579 AN XY: 720758

Gnomad4 AFR exome AF: 0.0334

Gnomad4 AMR exome AF: 0.00180

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000660

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00873 AC: 1327 AN: 152068 Hom.: 24 Cov.: 31 AF XY: 0.00835 AC XY: 621 AN XY: 74348

Gnomad4 AFR AF: 0.0305

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00428

Alfa AF: 0.00361 Hom.: 4

Bravo AF: 0.00972

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00281 AC: 341

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000179

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	19
Dann	Benign	0.97
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.99	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.072
Sift	Uncertain	0.013	D
Sift4G	Benign	0.19	T
Polyphen		0.033	B
Vest4		0.047
MVP		0.25
MPC		0.64
ClinPred		0.044	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.25

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: rs17882219; hg19: chr14-23306036;