rs4789860

Positions:

• chr17-78902551-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001243540.2(CEP295NL):​c.-99+583A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 152,236 control chromosomes in the GnomAD database, including 13,163 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 0.41 (13145 hom., cov: 32)
  • Exomes 𝑓: 0.40 (18 hom.)
• Consequence: CEP295NL NM_001243540.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.276

Genes affected

CEP295NL (HGNC:44659): (CEP295 N-terminal like) Predicted to enable microtubule binding activity. Predicted to be involved in regulation of centriole replication. Predicted to be located in motile cilium. Predicted to be active in centriole; centrosome; and cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP295NL	NM_001243540.2	c.-99+583A>G		intron_variant		ENST00000322630.3	NP_001230469.1
TIMP2	NM_003255.5	c.130+22408A>G		intron_variant		ENST00000262768.11	NP_003246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP2	ENST00000262768.11	c.130+22408A>G		intron_variant		1	NM_003255.5	ENSP00000262768	P1
CEP295NL	ENST00000322630.3	c.-99+583A>G		intron_variant		2	NM_001243540.2	ENSP00000312767	P1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62817 AN: 151932 Hom.: 13148 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.440

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.473

Gnomad MID AF: 0.471

Gnomad NFE AF: 0.409

Gnomad OTH AF: 0.424

GnomAD4 exome AF: 0.398 AC: 74 AN: 186 Hom.: 18 AF XY: 0.390 AC XY: 53 AN XY: 136

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.600

GnomAD4 genome AF: 0.413 AC: 62838 AN: 152050 Hom.: 13145 Cov.: 32 AF XY: 0.414 AC XY: 30803 AN XY: 74316

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.440

Gnomad4 EAS AF: 0.214

Gnomad4 SAS AF: 0.341

Gnomad4 FIN AF: 0.473

Gnomad4 NFE AF: 0.409

Gnomad4 OTH AF: 0.419

Alfa AF: 0.412 Hom.: 3124

Bravo AF: 0.408

Asia WGS AF: 0.260 AC: 904 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	4.4
DANN	Benign	0.23

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: rs4789860; hg19: chr17-76898633;