11-46701099-G-C

Variant names:

• chr11-46701099-G-C
• rs201062665
• NM_024741.3:c.52G>C

Variant summary

Our verdict is Uncertain significance. Variant got 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. 14/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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 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	c.52G>C	p.Ala18Pro	missense_variant, splice_region_variant	Exon 1 of 5	ENST00000311764.3	NP_079017.1
ZNF408	NM_001184751.2	c.-15G>C		5_prime_UTR_variant	Exon 1 of 5		NP_001171680.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249534 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135090

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 SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727214

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Benign	0.87
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.085
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.29		Gain of loop (P = 0.0013);
MVP		0.081
MPC		0.24
ClinPred		0.056	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.52

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

LitVar

Other links and lift over

dbSNP: rs201062665; hg19: chr11-46722649;