4-174299185-T-C

Variant names:

• chr4-174299185-T-C
• rs368228207
• NM_001040157.3:c.64T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001040157.3(CEP44):​c.64T>C​(p.Tyr22His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CEP44 NM_001040157.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP44	NM_001040157.3	c.64T>C	p.Tyr22His	missense_variant	Exon 3 of 12	ENST00000503780.6	NP_001035247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP44	ENST00000503780.6	c.64T>C	p.Tyr22His	missense_variant	Exon 3 of 12	1	NM_001040157.3	ENSP00000423153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461486 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727042

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.64T>C (p.Y22H) alteration is located in exon 3 (coding exon 1) of the CEP44 gene. This alteration results from a T to C substitution at nucleotide position 64, causing the tyrosine (Y) at amino acid position 22 to be replaced by a histidine (H). 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	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.;T;T;T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	.;.;.;D;D;D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.0	M;.;M;.;.;.;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;D;D
Vest4		0.90
MVP		0.93
MPC		0.50
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.78

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: rs368228207; hg19: chr4-175220336;