chr17-78873811-A-G

Variant names:

• chr17-78873811-A-G
• rs149597224
• NM_003255.5:c.231+8T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003255.5(TIMP2):​c.231+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000674 in 1,610,330 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: TIMP2 NM_003255.5 splice_region, intron
• Scores: Splicing: ADA: 0.00001175
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -3.49
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-78873811-A-G is Benign according to our data. Variant chr17-78873811-A-G is described in ClinVar as [Benign]. Clinvar id is 3033608.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP2	NM_003255.5	c.231+8T>C		splice_region_variant, intron_variant	Intron 2 of 4	ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP2	ENST00000262768.11	c.231+8T>C		splice_region_variant, intron_variant	Intron 2 of 4	1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes AF: 0.00339 AC: 515 AN: 151932 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00102 AC: 254 AN: 249830 AF XY: 0.000806

Gnomad AFR exome AF: 0.0140

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000387 AC: 565 AN: 1458280 Hom.: 3 Cov.: 30 AF XY: 0.000340 AC XY: 247 AN XY: 725766

African (AFR) AF: 0.0135 AC: 452 AN: 33444

American (AMR) AF: 0.000380 AC: 17 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39690

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51504

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110508

Other (OTH) AF: 0.000845 AC: 51 AN: 60322

GnomAD4 genome AF: 0.00342 AC: 520 AN: 152050 Hom.: 2 Cov.: 31 AF XY: 0.00331 AC XY: 246 AN XY: 74310

African (AFR) AF: 0.0119 AC: 492 AN: 41500

American (AMR) AF: 0.000525 AC: 8 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5148

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67966

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00171 Hom.: 1

Bravo AF: 0.00400

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TIMP2-related disorder Benign:1

Feb 18, 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	-0.83
CADD	Benign	0.18
DANN	Benign	0.66
PhyloP100		-3.5
PromoterAI		0.028	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000012
dbscSNV1_RF	Benign	0.034
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: rs149597224; hg19: chr17-76869893;