6-109153846-G-C

Variant names:

• chr6-109153846-G-C
• rs768328243
• NM_001271852.3:c.476G>C

Variant summary

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

The NM_001271852.3(CEP57L1):​c.476G>C​(p.Arg159Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,456,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CEP57L1 NM_001271852.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

Genes affected

CEP57L1 (HGNC:21561): (centrosomal protein 57 like 1) Enables identical protein binding activity. Predicted to be located in cytoplasm and microtubule. Predicted to be active 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=0.19534853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP57L1	NM_001271852.3	c.476G>C	p.Arg159Thr	missense_variant	Exon 5 of 11	ENST00000517392.6	NP_001258781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP57L1	ENST00000517392.6	c.476G>C	p.Arg159Thr	missense_variant	Exon 5 of 11	2	NM_001271852.3	ENSP00000427844.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1456736 Hom.: 0 Cov.: 28 AF XY: 0.00000552 AC XY: 4 AN XY: 724842

Gnomad4 AFR exome AF: 0.00

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: 0.00000811

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.476G>C (p.R159T) alteration is located in exon 7 (coding exon 4) of the CEP57L1 gene. This alteration results from a G to C substitution at nucleotide position 476, causing the arginine (R) at amino acid position 159 to be replaced by a threonine (T). 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	0.18
BayesDel_addAF	Benign	-0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.077	T;T;T;T;T;.;T;.;T;.;.;.;T;T;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.088
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.85	T;.;D;T;D;D;T;T;.;T;T;T;T;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.2	.;L;.;.;.;.;.;.;.;L;.;.;.;.;.;L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.045
Sift	Uncertain	0.0080	D;T;T;T;D;T;T;D;D;D;T;D;T;T;T;T
Sift4G	Benign	0.078	T;T;D;T;T;T;T;T;D;T;T;T;T;T;T;T
Polyphen		0.38	B;P;B;.;.;.;.;.;B;.;.;.;.;.;.;P
Vest4		0.34
MVP		0.78
MPC		0.28
ClinPred		0.71	D
GERP RS		0.72
Varity_R		0.17
gMVP		0.13

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: rs768328243; hg19: chr6-109475049;