dbSNP rs1323466852: ZWILCH:p.His194Asp (chr15-66520649-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_017975.5(ZWILCH):c.580C>G(p.His194Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,400,254 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. H194Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ZWILCH
NM_017975.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.14

Publications

0 publications found

Variant links:

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 links:

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]

RPL4 links:

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ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZWILCH	NM_017975.5	MANE Select	c.580C>G	p.His194Asp	missense	Exon 6 of 19	NP_060445.3
ZWILCH	NM_001287821.2		c.238C>G	p.His80Asp	missense	Exon 6 of 19	NP_001274750.1	Q9H900-2
ZWILCH	NM_001287822.2		c.238C>G	p.His80Asp	missense	Exon 5 of 18	NP_001274751.1	Q9H900-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZWILCH	ENST00000307897.10	TSL:1 MANE Select	c.580C>G	p.His194Asp	missense	Exon 6 of 19	ENSP00000311429.5	Q9H900-1
ZWILCH	ENST00000446801.6	TSL:1	c.238C>G	p.His80Asp	missense	Exon 6 of 19	ENSP00000402217.2	Q9H900-2
ZWILCH	ENST00000880580.1		c.580C>G	p.His194Asp	missense	Exon 6 of 19	ENSP00000550639.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1400254

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698452

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31942

American (AMR)

AF:

0.0000240

AC:

AN:

41594

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.00

AC:

AN:

83042

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062802

Other (OTH)

AF:

0.00

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

M_CAP

Benign

0.0076

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

PhyloP100

3.1

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.0

REVEL

Benign

0.12

Sift

Benign

0.29

Sift4G

Uncertain

0.022

Polyphen

0.38

Vest4

0.63

MutPred

0.62

Loss of MoRF binding (P = 0.0789)

MVP

0.46

MPC

0.055

ClinPred

0.97

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over