rs1561320546

Variant names:

• chr5-69191802-G-A
• rs1561320546
• NM_022909.4:c.142G>A

Variant summary

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

The NM_022909.4(CENPH):​c.142G>A​(p.Ala48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CENPH NM_022909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.17
• Publications: 0 publications found

Genes affected

CENPH (HGNC:17268): (centromere protein H) Centromere and kinetochore proteins play a critical role in centromere structure, kinetochore formation, and sister chromatid separation. The protein encoded by this gene colocalizes with inner kinetochore plate proteins CENP-A and CENP-C in both interphase and metaphase. It localizes outside of centromeric heterochromatin, where CENP-B is localized, and inside the kinetochore corona, where CENP-E is localized during prometaphase. It is thought that this protein can bind to itself, as well as to CENP-A, CENP-B or CENP-C. Multimers of the protein localize constitutively to the inner kinetochore plate and play an important role in the organization and function of the active centromere-kinetochore complex. [provided by RefSeq, Jul 2008]

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=0.24811399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CENPH	NM_022909.4	c.142G>A	p.Ala48Thr	missense_variant	Exon 2 of 9	ENST00000283006.7	NP_075060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CENPH	ENST00000283006.7	c.142G>A	p.Ala48Thr	missense_variant	Exon 2 of 9	1	NM_022909.4	ENSP00000283006.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1400842 Hom.: 0 Cov.: 24 AF XY: 0.00000143 AC XY: 1 AN XY: 700906

⚠️ 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: 32164

American (AMR) AF: 0.00 AC: 0 AN: 44212

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25706

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39302

South Asian (SAS) AF: 0.00 AC: 0 AN: 84838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5652

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1057352

Other (OTH) AF: 0.00 AC: 0 AN: 58240

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.006664), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142G>A (p.A48T) alteration is located in exon 2 (coding exon 2) of the CENPH gene. This alteration results from a G to A substitution at nucleotide position 142, causing the alanine (A) at amino acid position 48 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	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T;T
Eigen	Benign	-0.053
Eigen_PC	Benign	-0.018
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		1.2
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.054
Sift	Benign	0.091	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.0060	B;B
Vest4		0.18
MutPred		0.60		Gain of phosphorylation at A48 (P = 0.03);Gain of phosphorylation at A48 (P = 0.03);
MVP		0.53
MPC		0.058
ClinPred		0.21	T
GERP RS		3.2
Varity_R		0.057
gMVP		0.043
Mutation Taster		=88/12	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: rs1561320546; hg19: chr5-68487629;