3-138498109-T-C

Position:

• chr3-138498109-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024491.4(CEP70):​c.1654A>G​(p.Ile552Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,459,456 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP70 NM_024491.4 missense, splice_region
• Scores: Splicing: ADA: 0.01626
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

CEP70 (HGNC:29972): (centrosomal protein 70) Enables identical protein binding activity. Predicted to be involved in cilium assembly and regulation of microtubule cytoskeleton organization. Located in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2387873).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP70	NM_024491.4	c.1654A>G	p.Ile552Val	missense_variant, splice_region_variant	17/18	ENST00000264982.8	NP_077817.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP70	ENST00000264982.8	c.1654A>G	p.Ile552Val	missense_variant, splice_region_variant	17/18	1	NM_024491.4	ENSP00000264982.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459456 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726026

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2024

The c.1654A>G (p.I552V) alteration is located in exon 17 (coding exon 15) of the CEP70 gene. This alteration results from a A to G substitution at nucleotide position 1654, causing the isoleucine (I) at amino acid position 552 to be replaced by a valine (V). 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	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.;T;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;D;D;D;D
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;.;M;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.39	N;N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.42	T;T;T;T;T
Sift4G	Benign	0.25	T;T;T;T;T
Polyphen		1.0	D;P;D;.;.
Vest4		0.46
MutPred		0.30		Loss of helix (P = 0.0041);.;Loss of helix (P = 0.0041);.;.;
MVP		0.52
MPC		0.16
ClinPred		0.91	D
GERP RS		5.3
Varity_R		0.053
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.016
dbscSNV1_RF	Benign	0.058
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: rs2034113077; hg19: chr3-138216951;