4-174310785-T-A

Variant names:

• chr4-174310785-T-A
• rs1198928558
• NM_001040157.3:c.888T>A

Variant summary

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

The NM_001040157.3(CEP44):​c.888T>A​(p.Asn296Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000799 in 1,251,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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: 8.0e-7 (0 hom.)
• Consequence: CEP44 NM_001040157.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03

Genes affected

CEP44 (HGNC:29356): (centrosomal protein 44) Enables microtubule binding activity. Involved in centriole replication and centriole-centriole cohesion. Located in centriole; centrosome; and spindle pole. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP44	NM_001040157.3	c.888T>A	p.Asn296Lys	missense_variant, splice_region_variant	Exon 9 of 12	ENST00000503780.6	NP_001035247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP44	ENST00000503780.6	c.888T>A	p.Asn296Lys	missense_variant, splice_region_variant	Exon 9 of 12	1	NM_001040157.3	ENSP00000423153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.99e-7 AC: 1 AN: 1251066 Hom.: 0 Cov.: 18 AF XY: 0.00000158 AC XY: 1 AN XY: 631780

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: 0.00000106

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.888T>A (p.N296K) alteration is located in exon 9 (coding exon 7) of the CEP44 gene. This alteration results from a T to A substitution at nucleotide position 888, causing the asparagine (N) at amino acid position 296 to be replaced by a lysine (K). 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	0.12
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.17
DEOGEN2	Benign	0.0023	T;.;T;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.66	.;.;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;L
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.30	N;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.74	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0060	B;B;B;B
Vest4		0.24
MutPred		0.24		Gain of ubiquitination at N296 (P = 0.0247);Gain of ubiquitination at N296 (P = 0.0247);Gain of ubiquitination at N296 (P = 0.0247);Gain of ubiquitination at N296 (P = 0.0247);
MVP		0.26
MPC		0.095
ClinPred		0.040	T
GERP RS		1.6
Varity_R		0.042
gMVP		0.035

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1198928558; hg19: chr4-175231936;