11-46701052-A-T

Variant summary

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

The NM_024741.3(ZNF408):​c.5A>T​(p.Glu2Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ZNF408
NM_024741.3 missense

Scores

1
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0560
Variant links:
Genes affected
ZNF408 (HGNC:20041): (zinc finger protein 408) The protein encoded by this gene contains ten tandem zinc fingers and an N-terminal SET domain, so it is likely a DNA binding protein that interacts with other proteins. In adults, the encoded protein is expressed most highly in retina. Consequently, defects in this gene have been associated with familial exudative vitreoretinopathy (FEVR) and retinitis pigmentosa (RP). [provided by RefSeq, Dec 2016]

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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=0.2234911).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF408NM_024741.3 linkc.5A>T p.Glu2Val missense_variant Exon 1 of 5 ENST00000311764.3 NP_079017.1 Q9H9D4
ZNF408NM_001184751.2 linkc.-62A>T 5_prime_UTR_variant Exon 1 of 5 NP_001171680.1 Q9H9D4B4DXY4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF408ENST00000311764.3 linkc.5A>T p.Glu2Val missense_variant Exon 1 of 5 1 NM_024741.3 ENSP00000309606.2 Q9H9D4
ZNF408ENST00000526410.1 linkn.22A>T non_coding_transcript_exon_variant Exon 1 of 3 3
ZNF408ENST00000531866.1 linkn.23A>T non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461816
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727214
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
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
Cov.:
33
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 2 of the ZNF408 protein (p.Glu2Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ZNF408-related conditions. ClinVar contains an entry for this variant (Variation ID: 1384045). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.066
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
23
DANN
Uncertain
0.97
DEOGEN2
Benign
0.013
T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Benign
0.062
N
LIST_S2
Benign
0.37
T
M_CAP
Benign
0.0041
T
MetaRNN
Benign
0.22
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L
PROVEAN
Benign
-0.76
N
REVEL
Benign
0.094
Sift
Uncertain
0.0010
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.97
D
Vest4
0.36
MutPred
0.20
Gain of loop (P = 0.0166);
MVP
0.38
MPC
0.22
ClinPred
0.87
D
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1
Varity_R
0.25
gMVP
0.35

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.

Other links and lift over

dbSNP: rs1336848932; hg19: chr11-46722602; API