rs3918270

Variant names:

• chr20-46016700-G-A
• rs3918270
• ENST00000535913.2:n.669-1912C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000535913.2(SLC12A5-AS1):​n.669-1912C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 348,140 control chromosomes in the GnomAD database, including 5,117 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (1923 hom., cov: 30)
  • Exomes 𝑓: 0.16 (3194 hom.)
• Consequence: SLC12A5-AS1 ENST00000535913.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.34
• Publications: 20 publications found

Genes affected

SLC12A5-AS1 (HGNC:53143): (SLC12A5 and MMP9 antisense RNA 1)

MMP9 (HGNC:7176): (matrix metallopeptidase 9) 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. The enzyme encoded by this gene degrades type IV and V collagens. Studies in rhesus monkeys suggest that the enzyme is involved in IL-8-induced mobilization of hematopoietic progenitor cells from bone marrow, and murine studies suggest a role in tumor-associated tissue remodeling. [provided by RefSeq, Jul 2008]

MMP9 Gene-Disease associations (from GenCC):

• metaphyseal anadysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• metaphyseal anadysplasia 2

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC12A5-AS1	NR_147699.1	n.669-1912C>T		intron_variant	Intron 2 of 2
MMP9	NM_004994.3	c.*332G>A		downstream_gene_variant		ENST00000372330.3	NP_004985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC12A5-AS1	ENST00000535913.2	n.669-1912C>T		intron_variant	Intron 2 of 2	2
MMP9	ENST00000372330.3	c.*332G>A		downstream_gene_variant		1	NM_004994.3	ENSP00000361405.3

Frequencies

GnomAD3 genomes AF: 0.155 AC: 23435 AN: 151274 Hom.: 1925 Cov.: 30

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0933

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.135

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.151

GnomAD4 exome AF: 0.161 AC: 31671 AN: 196754 Hom.: 3194 AF XY: 0.174 AC XY: 18727 AN XY: 107662

African (AFR) AF: 0.158 AC: 872 AN: 5512

American (AMR) AF: 0.0740 AC: 685 AN: 9258

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 629 AN: 4728

East Asian (EAS) AF: 0.117 AC: 971 AN: 8312

South Asian (SAS) AF: 0.281 AC: 10530 AN: 37456

European-Finnish (FIN) AF: 0.155 AC: 1301 AN: 8390

Middle Eastern (MID) AF: 0.150 AC: 103 AN: 688

European-Non Finnish (NFE) AF: 0.134 AC: 15149 AN: 112654

Other (OTH) AF: 0.147 AC: 1431 AN: 9756

GnomAD4 genome AF: 0.155 AC: 23449 AN: 151386 Hom.: 1923 Cov.: 30 AF XY: 0.157 AC XY: 11577 AN XY: 73938

African (AFR) AF: 0.171 AC: 7060 AN: 41224

American (AMR) AF: 0.0930 AC: 1418 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 545 AN: 3464

East Asian (EAS) AF: 0.149 AC: 762 AN: 5122

South Asian (SAS) AF: 0.299 AC: 1433 AN: 4786

European-Finnish (FIN) AF: 0.169 AC: 1758 AN: 10376

Middle Eastern (MID) AF: 0.137 AC: 40 AN: 292

European-Non Finnish (NFE) AF: 0.148 AC: 10037 AN: 67868

Other (OTH) AF: 0.154 AC: 324 AN: 2102

Alfa AF: 0.160 Hom.: 284

Bravo AF: 0.147

Asia WGS AF: 0.206 AC: 713 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.99
DANN	Benign	0.51
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3918270; hg19: chr20-44645339;