rs1051121

Positions:

• chr11-102795242-C-T

Variant summary

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

The NM_002421.4(MMP1):​c.831G>A​(p.Ala277=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,613,932 control chromosomes in the GnomAD database, including 715 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (49 hom., cov: 33)
  • Exomes 𝑓: 0.028 (666 hom.)
• Consequence: MMP1 NM_002421.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.24

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=-0.58).
• BP6: Variant 11-102795242-C-T is Benign according to our data. Variant chr11-102795242-C-T is described in ClinVar as [Benign]. Clinvar id is 403091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-102795242-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.24 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMP1	NM_002421.4	c.831G>A	p.Ala277=	synonymous_variant	6/10	ENST00000315274.7	NP_002412.1
WTAPP1	NR_038390.1	n.583+18C>T		intron_variant, non_coding_transcript_variant
MMP1	NM_001145938.2	c.633G>A	p.Ala211=	synonymous_variant	6/10		NP_001139410.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMP1	ENST00000315274.7	c.831G>A	p.Ala277=	synonymous_variant	6/10	1	NM_002421.4	ENSP00000322788	P1
WTAPP1	ENST00000371455.7	n.325-2782C>T		intron_variant, non_coding_transcript_variant		4
WTAPP1	ENST00000525739.6	n.583+18C>T		intron_variant, non_coding_transcript_variant		2
WTAPP1	ENST00000544704.1	n.345-2782C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3162 AN: 152146 Hom.: 49 Cov.: 33

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0245

Gnomad ASJ AF: 0.0528

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00774

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0301

Gnomad OTH AF: 0.0258

GnomAD3 exomes AF: 0.0209 AC: 5230 AN: 250400 Hom.: 97 AF XY: 0.0221 AC XY: 2990 AN XY: 135340

Gnomad AFR exome AF: 0.00771

Gnomad AMR exome AF: 0.0167

Gnomad ASJ exome AF: 0.0572

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.0294

Gnomad OTH exome AF: 0.0306

GnomAD4 exome AF: 0.0277 AC: 40535 AN: 1461668 Hom.: 666 Cov.: 30 AF XY: 0.0278 AC XY: 20204 AN XY: 727140

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.0173

Gnomad4 ASJ exome AF: 0.0575

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0111

Gnomad4 FIN exome AF: 0.00719

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0208 AC: 3163 AN: 152264 Hom.: 49 Cov.: 33 AF XY: 0.0198 AC XY: 1471 AN XY: 74436

Gnomad4 AFR AF: 0.00736

Gnomad4 AMR AF: 0.0245

Gnomad4 ASJ AF: 0.0528

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00774

Gnomad4 NFE AF: 0.0301

Gnomad4 OTH AF: 0.0255

Alfa AF: 0.0270 Hom.: 34

Bravo AF: 0.0210

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0324

EpiControl AF: 0.0343

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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: Silent variant not in splice consensus -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.61

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: rs1051121; hg19: chr11-102665973; COSMIC: COSV59512157;