Genetic Variant ZCCHC7:p.Tyr36Cys (chr9-37126439-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032226.3(ZCCHC7):c.107A>G(p.Tyr36Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000821 in 1,461,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ZCCHC7
NM_032226.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.33

Variant links:

Genes affected

ZCCHC7 (HGNC:26209): (zinc finger CCHC-type containing 7) Enables RNA binding activity. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ZCCHC7 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZCCHC7	NM_032226.3 link	c.107A>G	p.Tyr36Cys	missense_variant	Exon 2 of 9	ENST00000336755.10	NP_115602.2	Q8N3Z6-1Q05DN1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZCCHC7	ENST00000336755.10 link	c.107A>G	p.Tyr36Cys	missense_variant	Exon 2 of 9	2	NM_032226.3	ENSP00000337839.5	Q8N3Z6-1
ZCCHC7	ENST00000534928.5 link	c.107A>G	p.Tyr36Cys	missense_variant	Exon 2 of 9	1		ENSP00000443113.2	Q8N3Z6-1
ZCCHC7	ENST00000322831.6 link	c.104A>G	p.Tyr35Cys	missense_variant	Exon 3 of 4	1		ENSP00000316365.6	X6R4A7
ZCCHC7	ENST00000461038.5 link	n.387A>G		non_coding_transcript_exon_variant	Exon 2 of 9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250034

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135296

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461606

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000660

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.107A>G (p.Y36C) alteration is located in exon 2 (coding exon 1) of the ZCCHC7 gene. This alteration results from a A to G substitution at nucleotide position 107, causing the tyrosine (Y) at amino acid position 36 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.20

T;T;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.033

MutationAssessor

Uncertain

2.1

M;M;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;D;D

REVEL

Uncertain

0.47

Sift

Uncertain

0.0030

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.88

MVP

0.47

MPC

0.57

ClinPred

0.87

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.38

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over