dbSNP rs77036618: ZCCHC4:p.Gln159Lys (chr4-25333328-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024936.3(ZCCHC4):c.475C>A(p.Gln159Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,060 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0068 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 15 hom. )

Consequence

ZCCHC4
NM_024936.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.10

Publications

3 publications found

Variant links:

Genes affected

ZCCHC4 (HGNC:22917): (zinc finger CCHC-type containing 4) Enables S-adenosyl-L-methionine binding activity; rRNA (adenine-N6-)-methyltransferase activity; and zinc ion binding activity. Involved in positive regulation of translation and rRNA methylation. Located in cytoplasm and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC4 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=0.0045552254).

BP6

Variant 4-25333328-C-A is Benign according to our data. Variant chr4-25333328-C-A is described in ClinVar as Benign. ClinVar VariationId is 720330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00678 (1032/152244) while in subpopulation AFR AF = 0.0233 (969/41538). AF 95% confidence interval is 0.0221. There are 11 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024936.3. 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
	ZCCHC4	NM_024936.3	MANE Select	c.475C>A	p.Gln159Lys	missense	Exon 4 of 13	NP_079212.2
	ZCCHC4	NM_001318148.2		c.475C>A	p.Gln159Lys	missense	Exon 4 of 9	NP_001305077.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZCCHC4	ENST00000302874.9	TSL:1 MANE Select	c.475C>A	p.Gln159Lys	missense	Exon 4 of 13	ENSP00000303468.4	Q9H5U6-1
ZCCHC4	ENST00000505451.5	TSL:1	n.500C>A		non_coding_transcript_exon	Exon 4 of 9
ZCCHC4	ENST00000507760.5	TSL:1	n.475C>A		non_coding_transcript_exon	Exon 4 of 9	ENSP00000422115.1	Q9H5U6-2

Frequencies

GnomAD3 genomes

AF:

0.00673

AC:

1024

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.00183

AC:

457

AN:

249526

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.0251

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.000790

AC:

1155

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000701

AC XY:

510

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0275

AC:

919

AN:

33474

American (AMR)

AF:

0.00157

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.000162

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111994

Other (OTH)

AF:

0.00220

AC:

133

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

135

202

270

337

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00678

AC:

1032

AN:

152244

Hom.:

Cov.:

AF XY:

0.00648

AC XY:

482

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0233

AC:

969

AN:

41538

American (AMR)

AF:

0.00307

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68020

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00248

Hom.:

Bravo

AF:

0.00822

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00220

AC:

266

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

0.078

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0068

Eigen

Benign

-0.051

Eigen_PC

Benign

-0.068

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0046

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

REVEL

Benign

0.036

Sift

Benign

0.10

Sift4G

Benign

0.23

Polyphen

0.0020

Vest4

0.20

MVP

0.055

MPC

0.10

ClinPred

0.0043

GERP RS

4.1

PromoterAI

-0.014

Neutral

(source)

Varity_R

0.37

gMVP

0.44

Mutation Taster

=88/12

polymorphism

(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