15-66527321-C-A

Variant names:

• chr15-66527321-C-A
• NM_017975.5:c.851C>A

Variant summary

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

The NM_017975.5(ZWILCH):​c.851C>A​(p.Thr284Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZWILCH NM_017975.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.89
• 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]

ZWILCH Gene-Disease associations (from GenCC):

• autism spectrum disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

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.851C>A	p.Thr284Asn	missense	Exon 9 of 19	NP_060445.3
	ZWILCH	NM_001287821.2		c.509C>A	p.Thr170Asn	missense	Exon 9 of 19	NP_001274750.1	Q9H900-2
	ZWILCH	NM_001287822.2		c.509C>A	p.Thr170Asn	missense	Exon 8 of 18	NP_001274751.1	Q9H900-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZWILCH	ENST00000307897.10	TSL:1 MANE Select	c.851C>A	p.Thr284Asn	missense	Exon 9 of 19	ENSP00000311429.5	Q9H900-1
	ZWILCH	ENST00000446801.6	TSL:1	c.509C>A	p.Thr170Asn	missense	Exon 9 of 19	ENSP00000402217.2	Q9H900-2
	ZWILCH	ENST00000880580.1		c.851C>A	p.Thr284Asn	missense	Exon 9 of 19	ENSP00000550639.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461796 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727198

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00109982), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

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	0.28
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.20
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.018	D
Polyphen		0.96	D
Vest4		0.49
MutPred		0.58		Loss of sheet (P = 0.1907)
MVP		0.70
MPC		0.15
ClinPred		0.97	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.43
Mutation Taster		=57/43	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

hg19: chr15-66819659; COSMIC: COSV105147980; COSMIC: COSV105147980;