rs1031019474

Variant names:

• chr17-78925022-G-A
• rs1031019474
• NM_003255.5:c.67C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003255.5(TIMP2):​c.67C>T​(p.Pro23Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000153 in 1,279,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TIMP2 NM_003255.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.812
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11226177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP2	NM_003255.5	c.67C>T	p.Pro23Ser	missense_variant	Exon 1 of 5	ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP2	ENST00000262768.11	c.67C>T	p.Pro23Ser	missense_variant	Exon 1 of 5	1	NM_003255.5	ENSP00000262768.6

Frequencies

GnomAD3 genomes AF: 0.000193 AC: 29 AN: 150488 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000991

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.000483

GnomAD2 exomes AF: 0.00 AC: 0 AN: 39962 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 167 AN: 1128650 Hom.: 0 Cov.: 30 AF XY: 0.000148 AC XY: 81 AN XY: 545512

African (AFR) AF: 0.0000434 AC: 1 AN: 23020

American (AMR) AF: 0.000594 AC: 8 AN: 13478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16630

East Asian (EAS) AF: 0.00 AC: 0 AN: 25016

South Asian (SAS) AF: 0.00 AC: 0 AN: 37578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3106

European-Non Finnish (NFE) AF: 0.000160 AC: 150 AN: 936576

Other (OTH) AF: 0.000182 AC: 8 AN: 43984

GnomAD4 genome AF: 0.000193 AC: 29 AN: 150488 Hom.: 0 Cov.: 30 AF XY: 0.000204 AC XY: 15 AN XY: 73502

African (AFR) AF: 0.0000243 AC: 1 AN: 41138

American (AMR) AF: 0.000991 AC: 15 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000178 AC: 12 AN: 67594

Other (OTH) AF: 0.000483 AC: 1 AN: 2070

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000382

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.67C>T (p.P23S) alteration is located in exon 1 (coding exon 1) of the TIMP2 gene. This alteration results from a C to T substitution at nucleotide position 67, causing the proline (P) at amino acid position 23 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.65	N
PhyloP100		0.81
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.22
Sift	Benign	0.52	T
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.048
MutPred		0.35		Gain of relative solvent accessibility (P = 0.0479);
MVP		0.12
MPC		0.69
ClinPred		0.037	T
GERP RS		0.74
PromoterAI		-0.010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.29
Mutation Taster		=92/8	polymorphism

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: rs1031019474; hg19: chr17-76921104;