rs553551503

Variant names:

• chr22-41943648-G-A
• rs553551503
• NM_024053.5:c.364C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-41943648-G-A
• chr22-41943648-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024053.5(CENPM):​c.364C>T​(p.His122Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,572 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H122D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CENPM NM_024053.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.405
• Publications: 0 publications found

Genes affected

CENPM (HGNC:18352): (centromere protein M) The protein encoded by this gene is an inner protein of the kinetochore, the multi-protein complex that binds spindle microtubules to regulate chromosome segregation during cell division. It belongs to the constitutive centromere-associated network protein group, whose members interact with outer kinetochore proteins and help to maintain centromere identity at each cell division cycle. The protein is structurally related to GTPases but cannot bind guanosine triphosphate. A point mutation that affects interaction with another constitutive centromere-associated network protein, CENP-I, impairs kinetochore assembly and chromosome alignment, suggesting that it is required for kinetochore formation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1469624).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024053.5. 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
	CENPM	NM_024053.5	MANE Select	c.364C>T	p.His122Tyr	missense	Exon 5 of 6	NP_076958.1	Q9NSP4-1
	CENPM	NM_001304370.2		c.262C>T	p.His88Tyr	missense	Exon 4 of 5	NP_001291299.1	B1AHQ6
	CENPM	NM_001304372.2		c.347C>T	p.Pro116Leu	missense	Exon 4 of 5	NP_001291301.1	B1AHQ8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CENPM	ENST00000215980.10	TSL:1 MANE Select	c.364C>T	p.His122Tyr	missense	Exon 5 of 6	ENSP00000215980.5	Q9NSP4-1
	CENPM	ENST00000921396.1		c.481C>T	p.His161Tyr	missense	Exon 6 of 7	ENSP00000591455.1
	CENPM	ENST00000718240.1		c.262C>T	p.His88Tyr	missense	Exon 4 of 6	ENSP00000520685.1	A0ABB0MV82

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461572 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727084

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111892

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.029
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	M
PhyloP100		0.41
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.023
Sift	Benign	0.27	T
Sift4G	Benign	1.0	T
Polyphen		0.095	B
Vest4		0.30
MutPred		0.26		Loss of methylation at K119 (P = 0.0685)
MVP		0.26
MPC		0.44
ClinPred		0.071	T
GERP RS		1.9
Varity_R		0.13
gMVP		0.46
Mutation Taster		=93/7	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: rs553551503; hg19: chr22-42339652;