NM_003255.5:c.303G>A

Variant names:

• chr17-78870935-C-T
• rs2277698
• NM_003255.5:c.303G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BA1

The NM_003255.5(TIMP2):​c.303G>A​(p.Ser101Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,611,508 control chromosomes in the GnomAD database, including 13,842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1205 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12637 hom.)
• Consequence: TIMP2 NM_003255.5 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.10
• Publications: 70 publications found

Genes affected

TIMP2 (HGNC:11821): (TIMP metallopeptidase inhibitor 2) This gene is a member of the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to an inhibitory role against metalloproteinases, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 17-78870935-C-T is Benign according to our data. Variant chr17-78870935-C-T is described in ClinVar as [Benign]. Clinvar id is 3059644.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP2	NM_003255.5	c.303G>A	p.Ser101Ser	synonymous_variant	Exon 3 of 5	ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP2	ENST00000262768.11	c.303G>A	p.Ser101Ser	synonymous_variant	Exon 3 of 5	1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17850 AN: 152102 Hom.: 1208 Cov.: 32

Gnomad AFR AF: 0.0946

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.103

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.121

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.117

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.133 AC: 33339 AN: 249848 AF XY: 0.138

Gnomad AFR exome AF: 0.0923

Gnomad AMR exome AF: 0.0874

Gnomad ASJ exome AF: 0.100

Gnomad EAS exome AF: 0.225

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.126 AC: 184176 AN: 1459288 Hom.: 12637 Cov.: 31 AF XY: 0.129 AC XY: 93521 AN XY: 725800

African (AFR) AF: 0.0953 AC: 3184 AN: 33400

American (AMR) AF: 0.0910 AC: 4052 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 2683 AN: 26064

East Asian (EAS) AF: 0.176 AC: 6957 AN: 39510

South Asian (SAS) AF: 0.225 AC: 19259 AN: 85648

European-Finnish (FIN) AF: 0.122 AC: 6530 AN: 53344

Middle Eastern (MID) AF: 0.155 AC: 892 AN: 5760

European-Non Finnish (NFE) AF: 0.119 AC: 132628 AN: 1110732

Other (OTH) AF: 0.133 AC: 7991 AN: 60302

GnomAD4 genome AF: 0.117 AC: 17851 AN: 152220 Hom.: 1205 Cov.: 32 AF XY: 0.118 AC XY: 8794 AN XY: 74418

African (AFR) AF: 0.0946 AC: 3930 AN: 41542

American (AMR) AF: 0.104 AC: 1594 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 356 AN: 3472

East Asian (EAS) AF: 0.224 AC: 1160 AN: 5182

South Asian (SAS) AF: 0.223 AC: 1078 AN: 4824

European-Finnish (FIN) AF: 0.121 AC: 1286 AN: 10594

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.117 AC: 7981 AN: 68006

Other (OTH) AF: 0.118 AC: 249 AN: 2112

Alfa AF: 0.115 Hom.: 1652

Bravo AF: 0.115

Asia WGS AF: 0.203 AC: 707 AN: 3478

EpiCase AF: 0.119

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TIMP2-related disorder Benign:1

Jun 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	7.8
DANN	Benign	0.77
PhyloP100		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2277698; hg19: chr17-76867017; COSMIC: COSV53163572;