chr15-66514024-C-A

Variant names:

• chr15-66514024-C-A
• rs1595905134
• NM_017975.5:c.142C>A

Variant summary

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

The NM_017975.5(ZWILCH):​c.142C>A​(p.Pro48Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 6.8e-7 (0 hom.)
• Consequence: ZWILCH NM_017975.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256
• Publications: 0 publications found

Genes affected

ZWILCH (HGNC:25468): (zwilch kinetochore protein) Involved in protein localization to kinetochore. Located in kinetochore. Part of RZZ complex. [provided by Alliance of Genome Resources, Apr 2022]

RPL4 (HGNC:10353): (ribosomal protein L4) Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 60S subunit. The protein belongs to the L4E family of ribosomal proteins. It is located in the cytoplasm. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome. [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=0.07469711).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017975.5. 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
	ZWILCH	NM_017975.5	MANE Select	c.142C>A	p.Pro48Thr	missense	Exon 3 of 19	NP_060445.3
	ZWILCH	NM_001287821.2		c.-201C>A		5_prime_UTR	Exon 3 of 19	NP_001274750.1	Q9H900-2
	ZWILCH	NM_001287823.2		c.-201C>A		5_prime_UTR	Exon 2 of 18	NP_001274752.1	Q9H900-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZWILCH	ENST00000307897.10	TSL:1 MANE Select	c.142C>A	p.Pro48Thr	missense	Exon 3 of 19	ENSP00000311429.5	Q9H900-1
	ZWILCH	ENST00000446801.6	TSL:1	c.-201C>A		5_prime_UTR	Exon 3 of 19	ENSP00000402217.2	Q9H900-2
	ZWILCH	ENST00000880580.1		c.142C>A	p.Pro48Thr	missense	Exon 3 of 19	ENSP00000550639.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460456 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726486

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000299 AC: 1 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44490

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111324

Other (OTH) AF: 0.00 AC: 0 AN: 60324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.57
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.26
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.046
Sift	Benign	0.64	T
Sift4G	Benign	0.50	T
Polyphen		0.64	P
Vest4		0.12
MutPred		0.47		Loss of ubiquitination at K52 (P = 0.0516)
MVP		0.36
MPC		0.029
ClinPred		0.22	T
GERP RS		2.9
Varity_R		0.11
gMVP		0.17
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1595905134; hg19: chr15-66806362;