dbSNP rs369656009: ZCCHC9:p.Pro176Gln (chr5-81308703-C-A) – 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_001131035.2(ZCCHC9):c.527C>A(p.Pro176Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,454,498 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. P176L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZCCHC9
NM_001131035.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.69

Publications

0 publications found

Variant links:

Genes affected

ZCCHC9 (HGNC:25424): (zinc finger CCHC-type containing 9) Enables RNA binding activity. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC9 links:

ACOT12 (HGNC:24436): (acyl-CoA thioesterase 12) Enables identical protein binding activity. Predicted to be involved in acyl-CoA metabolic process and fatty acid metabolic process. Predicted to act upstream of or within acetyl-CoA metabolic process. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACOT12 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_001131035.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZCCHC9	NM_001131035.2	MANE Select	c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	NP_001124507.1	Q8N567
ZCCHC9	NM_001131036.2		c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	NP_001124508.1	Q8N567
ZCCHC9	NM_032280.3		c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	NP_115656.1	Q8N567

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZCCHC9	ENST00000407610.8	TSL:2 MANE Select	c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	ENSP00000385047.3	Q8N567
ZCCHC9	ENST00000380199.9	TSL:1	c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	ENSP00000369546.5	Q8N567
ZCCHC9	ENST00000438268.2	TSL:1	c.527C>A	p.Pro176Gln	missense	Exon 3 of 6	ENSP00000412637.2	Q8N567

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

244510

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1454498

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33194

American (AMR)

AF:

0.00

AC:

AN:

42700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25846

East Asian (EAS)

AF:

0.00

AC:

AN:

39488

South Asian (SAS)

AF:

0.00

AC:

AN:

84614

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53296

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1109548

Other (OTH)

AF:

0.00

AC:

AN:

60076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.600

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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.052

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.053

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.033

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.59

MutationAssessor

Uncertain

2.7

PhyloP100

3.7

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.23

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.51

MutPred

0.41

Gain of catalytic residue at P176 (P = 0.021)

MVP

0.44

MPC

0.48

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.29

gMVP

0.55

Mutation Taster

=48/52

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over