11-102795585-T-C

Position:

• chr11-102795585-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000315274.7(MMP1):​c.648A>G​(p.Ala216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.941 in 1,612,654 control chromosomes in the GnomAD database, including 715,451 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68631 hom., cov: 31)
  • Exomes 𝑓: 0.94 (646820 hom.)
• Consequence: MMP1 ENST00000315274.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.36

Genes affected

MMP1 (HGNC:7155): (matrix metallopeptidase 1) This gene encodes a member of the peptidase M10 family of matrix metalloproteinases (MMPs). Proteins in this 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. The encoded preproprotein is proteolytically processed to generate the mature protease. This secreted protease breaks down the interstitial collagens, including types I, II, and III. The gene is part of a cluster of MMP genes on chromosome 11. Mutations in this gene are associated with chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Jan 2016]

WTAPP1 (HGNC:44115): (WTAP pseudogene 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 11-102795585-T-C is Benign according to our data. Variant chr11-102795585-T-C is described in ClinVar as [Benign]. Clinvar id is 403092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-102795585-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP1	NM_002421.4	c.648A>G	p.Ala216=	synonymous_variant	5/10	ENST00000315274.7	NP_002412.1
WTAPP1	NR_038390.1	n.583+361T>C		intron_variant, non_coding_transcript_variant
MMP1	NM_001145938.2	c.450A>G	p.Ala150=	synonymous_variant	5/10		NP_001139410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP1	ENST00000315274.7	c.648A>G	p.Ala216=	synonymous_variant	5/10	1	NM_002421.4	ENSP00000322788	P1
WTAPP1	ENST00000371455.7	n.325-2439T>C		intron_variant, non_coding_transcript_variant		4
WTAPP1	ENST00000525739.6	n.583+361T>C		intron_variant, non_coding_transcript_variant		2
WTAPP1	ENST00000544704.1	n.345-2439T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.949 AC: 144315 AN: 152090 Hom.: 68573 Cov.: 31

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.932

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.921

Gnomad EAS AF: 0.894

Gnomad SAS AF: 0.904

Gnomad FIN AF: 0.917

Gnomad MID AF: 0.927

Gnomad NFE AF: 0.949

Gnomad OTH AF: 0.939

GnomAD3 exomes AF: 0.924 AC: 230883 AN: 249836 Hom.: 106984 AF XY: 0.926 AC XY: 124960 AN XY: 134968

Gnomad AFR exome AF: 0.989

Gnomad AMR exome AF: 0.845

Gnomad ASJ exome AF: 0.928

Gnomad EAS exome AF: 0.886

Gnomad SAS exome AF: 0.898

Gnomad FIN exome AF: 0.922

Gnomad NFE exome AF: 0.952

Gnomad OTH exome AF: 0.934

GnomAD4 exome AF: 0.941 AC: 1373872 AN: 1460448 Hom.: 646820 Cov.: 42 AF XY: 0.940 AC XY: 682628 AN XY: 726446

Gnomad4 AFR exome AF: 0.991

Gnomad4 AMR exome AF: 0.852

Gnomad4 ASJ exome AF: 0.929

Gnomad4 EAS exome AF: 0.884

Gnomad4 SAS exome AF: 0.898

Gnomad4 FIN exome AF: 0.927

Gnomad4 NFE exome AF: 0.949

Gnomad4 OTH exome AF: 0.939

GnomAD4 genome AF: 0.949 AC: 144431 AN: 152206 Hom.: 68631 Cov.: 31 AF XY: 0.945 AC XY: 70339 AN XY: 74404

Gnomad4 AFR AF: 0.988

Gnomad4 AMR AF: 0.903

Gnomad4 ASJ AF: 0.921

Gnomad4 EAS AF: 0.894

Gnomad4 SAS AF: 0.903

Gnomad4 FIN AF: 0.917

Gnomad4 NFE AF: 0.949

Gnomad4 OTH AF: 0.940

Alfa AF: 0.944 Hom.: 82445

Bravo AF: 0.948

Asia WGS AF: 0.912 AC: 3173 AN: 3478

EpiCase AF: 0.947

EpiControl AF: 0.946

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.18
DANN	Benign	0.49

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: rs470558; hg19: chr11-102666316;