chr15-66505387-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017975.5(ZWILCH):c.49C>T(p.Leu17Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00293 in 1,614,102 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 63 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 54 hom. )

Consequence

ZWILCH
NM_017975.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.849

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031256378).

BP6

Variant 15-66505387-C-T is Benign according to our data. Variant chr15-66505387-C-T is described in ClinVar as Benign. ClinVar VariationId is 785497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0548 is higher than 0.05.

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.49C>T	p.Leu17Phe	missense	Exon 1 of 19	NP_060445.3
ZWILCH	NM_001287821.2		c.-389C>T		5_prime_UTR	Exon 1 of 19	NP_001274750.1	Q9H900-2
ZWILCH	NM_001287822.2		c.-293C>T		5_prime_UTR	Exon 1 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.49C>T	p.Leu17Phe	missense	Exon 1 of 19	ENSP00000311429.5	Q9H900-1
ZWILCH	ENST00000446801.6	TSL:1	c.-389C>T		5_prime_UTR	Exon 1 of 19	ENSP00000402217.2	Q9H900-2
ZWILCH	ENST00000880580.1		c.49C>T	p.Leu17Phe	missense	Exon 1 of 19	ENSP00000550639.1

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2443

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0567

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.00403

AC:

1005

AN:

249590

AF XY:

0.00307

show subpopulations

Gnomad AFR exome

AF:

0.0567

Gnomad AMR exome

AF:

0.00148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00156

AC:

2274

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

988

AN XY:

727168

show subpopulations

African (AFR)

AF:

0.0571

AC:

1910

AN:

33466

American (AMR)

AF:

0.00208

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000928

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000800

AC:

AN:

1111948

Other (OTH)

AF:

0.00277

AC:

167

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

104

209

313

418

522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0161

AC:

2449

AN:

152362

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1164

AN XY:

74516

show subpopulations

African (AFR)

AF:

0.0567

AC:

2357

AN:

41568

American (AMR)

AF:

0.00412

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68040

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

126

252

377

503

629

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00398

Hom.:

Bravo

AF:

0.0177

ESP6500AA

AF:

0.0570

AC:

251

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00488

AC:

593

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0061

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.73

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

0.85

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.79

REVEL

Benign

0.037

Sift

Benign

0.078

Sift4G

Benign

0.085

Polyphen

0.97

Vest4

0.19

MVP

0.40

MPC

0.029

ClinPred

0.019

GERP RS

2.4

PromoterAI

0.024

Neutral

(source)

Varity_R

0.15

gMVP

0.21

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over