rs1894168062

Variant names:

• chr15-66514076-A-C
• rs1894168062
• NM_017975.5:c.194A>C

Variant summary

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

The NM_017975.5(ZWILCH):​c.194A>C​(p.Glu65Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ZWILCH NM_017975.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• 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 2 ACMG points.

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

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.194A>C	p.Glu65Ala	missense	Exon 3 of 19	NP_060445.3
	ZWILCH	NM_001287821.2		c.-149A>C		5_prime_UTR	Exon 3 of 19	NP_001274750.1	Q9H900-2
	ZWILCH	NM_001287823.2		c.-149A>C		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.194A>C	p.Glu65Ala	missense	Exon 3 of 19	ENSP00000311429.5	Q9H900-1
	ZWILCH	ENST00000446801.6	TSL:1	c.-149A>C		5_prime_UTR	Exon 3 of 19	ENSP00000402217.2	Q9H900-2
	ZWILCH	ENST00000880580.1		c.194A>C	p.Glu65Ala	missense	Exon 3 of 19	ENSP00000550639.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451582 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722004

African (AFR) AF: 0.00 AC: 0 AN: 33088

American (AMR) AF: 0.00 AC: 0 AN: 43328

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25768

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.00 AC: 0 AN: 84930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106734

Other (OTH) AF: 0.00 AC: 0 AN: 59800

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

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	Uncertain	0.40
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.31
Sift	Benign	0.035	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.38
MutPred		0.79		Loss of disorder (P = 0.0393)
MVP		0.69
MPC		0.17
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.28
gMVP		0.54
Mutation Taster		=54/46	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: rs1894168062; hg19: chr15-66806414;