rs796065315

Positions:

• chr11-46701476-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024741.3(ZNF408):​c.130C>T​(p.Pro44Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P44L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF408 NM_024741.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.622

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 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=0.075312346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF408	NM_024741.3	c.130C>T	p.Pro44Ser	missense_variant	2/5	ENST00000311764.3
ZNF408	NM_001184751.2	c.106C>T	p.Pro36Ser	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF408	ENST00000311764.3	c.130C>T	p.Pro44Ser	missense_variant	2/5	1	NM_024741.3	P1
ZNF408	ENST00000526410.1	n.147C>T		non_coding_transcript_exon_variant	2/3	3
ZNF408	ENST00000531866.1	n.148C>T		non_coding_transcript_exon_variant	2/2	2
ZNF408	ENST00000534481.1	n.269C>T		non_coding_transcript_exon_variant	1/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Exudative vitreoretinopathy 1 Uncertain:1

Uncertain significance, no assertion criteria provided

research

Hyderabad Eye Research Foundation, L V Prasad Eye Institute

Feb 12, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.7
DANN	Benign	0.86
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.0090
Sift	Benign	0.054	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.062	B
Vest4		0.24
MutPred		0.29		Loss of catalytic residue at P44 (P = 0.001);
MVP		0.040
MPC		0.19
ClinPred		0.24	T
GERP RS		0.54
Varity_R		0.027
gMVP		0.30

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

Other links and lift over

dbSNP: rs796065315; hg19: chr11-46723026;