Genetic Variant ZC3HAV1:p.Leu730Trp (chr7-139054094-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020119.4(ZC3HAV1):c.2189T>G(p.Leu730Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

ZC3HAV1
NM_020119.4 missense, splice_region

Scores

Splicing: ADA: 0.3781

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.46

Variant links:

Genes affected

ZC3HAV1 (HGNC:23721): (zinc finger CCCH-type containing, antiviral 1) This gene encodes a CCCH-type zinc finger protein. This antiviral protein inhibits viral replication by recruiting cellular RNA degradation machineries to degrade viral mRNAs. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses, including Ebola virus, HIV and SARS-CoV-2 (which causes COVID-19). [provided by RefSeq, Sep 2021]

ZC3HAV1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3HAV1	NM_020119.4 link	c.2189T>G	p.Leu730Trp	missense_variant, splice_region_variant	Exon 11 of 13	ENST00000242351.10	NP_064504.2	Q7Z2W4-1
ZC3HAV1	NM_001363491.2 link	c.2555T>G	p.Leu852Trp	missense_variant, splice_region_variant	Exon 11 of 13		NP_001350420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZC3HAV1	ENST00000242351.10 link	c.2189T>G	p.Leu730Trp	missense_variant, splice_region_variant	Exon 11 of 13	1	NM_020119.4	ENSP00000242351.5	Q7Z2W4-1
ZC3HAV1	ENST00000464606.5 link	c.2555T>G	p.Leu852Trp	missense_variant, splice_region_variant	Exon 11 of 13	5		ENSP00000418385.1	C9J6P4
ZC3HAV1	ENST00000680309.1 link	c.1754T>G	p.Leu585Trp	missense_variant, splice_region_variant	Exon 11 of 13			ENSP00000505045.1	A0A7P0T8C6

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2189T>G (p.L730W) alteration is located in exon 11 (coding exon 11) of the ZC3HAV1 gene. This alteration results from a T to G substitution at nucleotide position 2189, causing the leucine (L) at amino acid position 730 to be replaced by a tryptophan (W). 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

Uncertain

0.40

BayesDel_addAF

Benign

-0.081

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.15

T;T

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.088

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.44

T;T

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.59

D;D

MetaSVM

Benign

-0.83

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.2

D;D

REVEL

Benign

0.21

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.017

D;D

Polyphen

1.0

D;.

Vest4

0.50

MutPred

0.63

Loss of disorder (P = 0.0583);.;

MVP

0.21

MPC

1.0

ClinPred

0.97

GERP RS

4.7

Varity_R

0.52

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.38

dbscSNV1_RF

Benign

0.46

SpliceAI score (max)

0.16

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