11-46701091-T-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024741.3(ZNF408):c.44T>A(p.Leu15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L15L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF408 NM_024741.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.190

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06413633).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF408	NM_024741.3	c.44T>A	p.Leu15Gln	missense_variant	1/5	ENST00000311764.3
ZNF408	NM_001184751.2	c.-23T>A		5_prime_UTR_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF408	ENST00000311764.3	c.44T>A	p.Leu15Gln	missense_variant	1/5	1	NM_024741.3	P1
ZNF408	ENST00000526410.1	n.61T>A		non_coding_transcript_exon_variant	1/3	3
ZNF408	ENST00000531866.1	n.62T>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 15, 2019

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ZNF408-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with glutamine at codon 15 of the ZNF408 protein (p.Leu15Gln). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0028	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.044
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.037	B
Vest4		0.13
MutPred		0.20		Loss of helix (P = 0.028);
MVP		0.040
MPC		0.19
ClinPred		0.28	T
GERP RS		-4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs2064700135; hg19: chr11-46722641;