Genetic Variant NM_004995.4:c.-44G>C (chr14-22836774-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBA1

The NM_004995.4(MMP14):c.-44G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,336,282 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.015 ( 48 hom., cov: 31)

Exomes 𝑓: 0.0015 ( 53 hom. )

Consequence

MMP14
NM_004995.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.454

Publications

0 publications found

Variant links:

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]

MMP14 Gene-Disease associations (from GenCC):

Winchester syndrome
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
multicentric osteolysis-nodulosis-arthropathy spectrum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MMP14 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 14-22836774-G-C is Benign according to our data. Variant chr14-22836774-G-C is described in ClinVar as Benign. ClinVar VariationId is 1273921.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0501 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004995.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMP14	NM_004995.4	MANE Select	c.-44G>C		5_prime_UTR	Exon 1 of 10	NP_004986.1	P50281

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MMP14	ENST00000311852.11	TSL:1 MANE Select	c.-44G>C	5_prime_UTR	Exon 1 of 10	ENSP00000308208.6	P50281
MMP14	ENST00000928197.1		c.-44G>C	5_prime_UTR	Exon 1 of 10	ENSP00000598256.1
MMP14	ENST00000548162.2	TSL:5	c.-44G>C	5_prime_UTR	Exon 1 of 10	ENSP00000506068.1	A0A7P0TAG0

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

2262

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00398

AC:

549

AN:

137896

AF XY:

0.00325

show subpopulations

Gnomad AFR exome

AF:

0.0522

Gnomad AMR exome

AF:

0.00259

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000678

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.00154

AC:

1825

AN:

1183994

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

810

AN XY:

585006

show subpopulations

African (AFR)

AF:

0.0575

AC:

1497

AN:

26026

American (AMR)

AF:

0.00316

AC:

AN:

30104

Ashkenazi Jewish (ASJ)

AF:

0.0000503

AC:

AN:

19898

East Asian (EAS)

AF:

0.00

AC:

AN:

35072

South Asian (SAS)

AF:

0.0000590

AC:

AN:

67754

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46386

Middle Eastern (MID)

AF:

0.000643

AC:

AN:

4668

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

904100

Other (OTH)

AF:

0.00382

AC:

191

AN:

49986

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0149

AC:

2269

AN:

152288

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1035

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0519

AC:

2159

AN:

41562

American (AMR)

AF:

0.00496

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68018

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

105

209

314

418

523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00770

Hom.:

Bravo

AF:

0.0172

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.6

(source)

DANN

Benign

0.92

PhyloP100

-0.45

PromoterAI

-0.11

Neutral

(source)

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over