18-74635029-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_017757.3(ZNF407):c.4010A>G(p.Tyr1337Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ZNF407
NM_017757.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

ZNF407 (HGNC:19904): (zinc finger protein 407) This gene encodes a zinc finger protein whose exact function is not known. It may be involved in transcriptional regulation. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZNF407 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27647406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF407	NM_017757.3 linkuse as main transcript	c.4010A>G	p.Tyr1337Cys	missense_variant	2/9	ENST00000299687.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF407	ENST00000299687.10 linkuse as main transcript	c.4010A>G	p.Tyr1337Cys	missense_variant	2/9	1	NM_017757.3	P2	Q9C0G0-1
ZNF407	ENST00000577538.5 linkuse as main transcript	c.4010A>G	p.Tyr1337Cys	missense_variant	1/7	2		A2	Q9C0G0-2
ZNF407	ENST00000309902.10 linkuse as main transcript	c.4010A>G	p.Tyr1337Cys	missense_variant	1/4	2			Q9C0G0-3
ZNF407	ENST00000582337.5 linkuse as main transcript	c.4010A>G	p.Tyr1337Cys	missense_variant	2/5	5			Q9C0G0-3

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

248886

Hom.:

AF XY:

0.0000740

AC XY:

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

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:

0.00000887

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000693

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.000184

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000296

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00177

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000136

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 06, 2021	The c.4010A>G (p.Y1337C) alteration is located in exon 1 (coding exon 1) of the ZNF407 gene. This alteration results from a A to G substitution at nucleotide position 4010, causing the tyrosine (Y) at amino acid position 1337 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ZNF407-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 28, 2023

The ZNF407 c.4010A>G variant is predicted to result in the amino acid substitution p.Tyr1337Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.046% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-72346985-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.23

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.83

M_CAP

Benign

0.014

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M;M;M

MutationTaster

Benign

0.82

D;D;D;D

PrimateAI

Benign

0.48

Sift4G

Benign

0.075

T;T;T;T

Polyphen

1.0

D;D;D;D

Vest4

0.54

MutPred

0.59

Loss of phosphorylation at Y1337 (P = 0.0126);Loss of phosphorylation at Y1337 (P = 0.0126);Loss of phosphorylation at Y1337 (P = 0.0126);Loss of phosphorylation at Y1337 (P = 0.0126);

MVP

0.20

MPC

0.47

ClinPred

0.21

GERP RS

4.6

Varity_R

0.13

gMVP

0.17

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