Variant chr17-4016409-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015113.4(ZZEF1):c.8059G>T(p.Ala2687Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZZEF1
NM_015113.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.21

Variant links:

Genes affected

ZZEF1 (HGNC:29027): (zinc finger ZZ-type and EF-hand domain containing 1) Predicted to enable ubiquitin-like protein ligase activity. Predicted to act upstream of or within several processes, including glutamatergic synaptic transmission; regulation of peptidyl-tyrosine phosphorylation; and visual learning. Predicted to be located in cell surface; postsynapse; and presynaptic active zone. [provided by Alliance of Genome Resources, Apr 2022]

ZZEF1 links:

ZZEF1 (HGNC:):

ZZEF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13531831).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZZEF1	NM_015113.4 linkuse as main transcript	c.8059G>T	p.Ala2687Ser	missense_variant	49/55	ENST00000381638.7	NP_055928.3	O43149-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ZZEF1	ENST00000381638.7 linkuse as main transcript	c.8059G>T	p.Ala2687Ser	missense_variant	49/55	1	NM_015113.4	ENSP00000371051.2	O43149-1
ZZEF1	ENST00000572831.1 linkuse as main transcript	n.*134G>T		non_coding_transcript_exon_variant	3/4	4		ENSP00000459796.1	I3L2N1
ZZEF1	ENST00000573536.1 linkuse as main transcript	n.1172G>T		non_coding_transcript_exon_variant	1/5	2
ZZEF1	ENST00000572831.1 linkuse as main transcript	n.*134G>T		3_prime_UTR_variant	3/4	4		ENSP00000459796.1	I3L2N1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251352

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461768

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

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:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2024

The c.8059G>T (p.A2687S) alteration is located in exon 49 (coding exon 49) of the ZZEF1 gene. This alteration results from a G to T substitution at nucleotide position 8059, causing the alanine (A) at amino acid position 2687 to be replaced by a serine (S). 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

Benign

0.13

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.042

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0010

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0095

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.37

REVEL

Benign

0.039

Sift

Benign

0.036

Sift4G

Benign

0.077

Polyphen

0.055

Vest4

0.55

MutPred

0.26

Gain of sheet (P = 0.0827);

MVP

0.043

MPC

0.18

ClinPred

0.56

GERP RS

2.5

Varity_R

0.061

gMVP

0.13

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