chr1-243136167-A-G

Variant names:

• chr1-243136167-A-G
• rs1238396743
• NM_014812.3:c.4295T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014812.3(CEP170):​c.4295T>C​(p.Ile1432Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1432V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CEP170 NM_014812.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79
• Publications: 0 publications found

Genes affected

CEP170 (HGNC:28920): (centrosomal protein 170) The product of this gene is a component of the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. During interphase, the encoded protein localizes to the sub-distal appendages of mature centrioles, which are microtubule-based structures thought to help organize centrosomes. During mitosis, the protein associates with spindle microtubules near the centrosomes. The protein interacts with and is phosphorylated by polo-like kinase 1, and functions in maintaining microtubule organization and cell morphology. The human genome contains a putative transcribed pseudogene. Several alternatively spliced transcript variants of this gene have been found, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Jul 2008]

ENSG00000227230 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4178176).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014812.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP170	NM_014812.3	MANE Select	c.4295T>C	p.Ile1432Thr	missense	Exon 17 of 20	NP_055627.2	Q5SW79-1
	CEP170	NM_001042404.2		c.4001T>C	p.Ile1334Thr	missense	Exon 16 of 19	NP_001035863.1	Q5SW79-3
	CEP170	NM_001042405.2		c.3923T>C	p.Ile1308Thr	missense	Exon 16 of 19	NP_001035864.1	Q5SW79-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP170	ENST00000366542.6	TSL:5 MANE Select	c.4295T>C	p.Ile1432Thr	missense	Exon 17 of 20	ENSP00000355500.1	Q5SW79-1
	CEP170	ENST00000366544.6	TSL:5	c.4001T>C	p.Ile1334Thr	missense	Exon 16 of 19	ENSP00000355502.1	Q5SW79-3
	CEP170	ENST00000366543.5	TSL:5	c.3923T>C	p.Ile1308Thr	missense	Exon 16 of 19	ENSP00000355501.1	Q5SW79-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000771 AC: 1 AN: 129700 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000629

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 Data not reliable, filtered out with message: AS_VQSR AF: 7.26e-7 AC: 1 AN: 1377524 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 679370

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30612

American (AMR) AF: 0.0000323 AC: 1 AN: 30932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24756

East Asian (EAS) AF: 0.00 AC: 0 AN: 35514

South Asian (SAS) AF: 0.00 AC: 0 AN: 76404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5624

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067300

Other (OTH) AF: 0.00 AC: 0 AN: 57208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	0.0061	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.096
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		6.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.69	T
Sift4G	Benign	0.88	T
Polyphen		0.91	P
Vest4		0.69
MutPred		0.32		Loss of stability (P = 0.0057)
MVP		0.65
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.081
gMVP		0.20
Mutation Taster		=51/49	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: rs1238396743; hg19: chr1-243299469;