11-46701099-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024741.3(ZNF408):c.52G>C(p.Ala18Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/25 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A18V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF408
NM_024741.3 missense, splice_region

Scores

Splicing: ADA: 0.9849

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.431

Publications

1 publications found

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]

ZNF408 Gene-Disease associations (from GenCC):

exudative vitreoretinopathy 6
Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
retinitis pigmentosa 72
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
exudative vitreoretinopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ZNF408 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
ZNF408	NM_024741.3 link	c.52G>C	p.Ala18Pro	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000311764.3	NP_079017.1	Q9H9D4
ZNF408	NM_001184751.2 link	c.-15G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001171680.1	Q9H9D4B4DXY4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF408	ENST00000311764.3 link	c.52G>C	p.Ala18Pro	missense_variant, splice_region_variant	Exon 1 of 5	1	NM_024741.3	ENSP00000309606.2	Q9H9D4
ZNF408	ENST00000526410.1 link	n.69G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 3	3
ZNF408	ENST00000531866.1 link	n.70G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 2	2
ZNF408	ENST00000534481.1 link	n.-109G>C		upstream_gene_variant		4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249534

AF XY:

0.00000740

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.019

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.40

M_CAP

Benign

0.0037

MetaRNN

Benign

0.062

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.46

PhyloP100

0.43

PROVEAN

Benign

-0.72

REVEL

Benign

0.085

Sift

Benign

0.12

Sift4G

Uncertain

0.0070

Polyphen

0.0020

Vest4

0.17

MutPred

0.29

Gain of loop (P = 0.0013);

MVP

0.081

MPC

0.24

ClinPred

0.056

GERP RS

1.5

PromoterAI

-0.32

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.52

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.62

SpliceAI score (max)

0.47

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.47

Position offset: 42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over