11-46701135-G-C

Variant names:

• chr11-46701135-G-C
• rs111794632
• NM_024741.3:c.52+36G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001184751.2(ZNF408):​c.22G>C​(p.Gly8Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,928 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0058 (9 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (16 hom.)
• Consequence: ZNF408 NM_001184751.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.160

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 11-46701135-G-C is Benign according to our data. Variant chr11-46701135-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1206255.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-46701135-G-C is described in Lovd as [Benign]. Variant chr11-46701135-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00577 (878/152288) while in subpopulation AFR AF= 0.0135 (560/41554). AF 95% confidence interval is 0.0126. There are 9 homozygotes in gnomad4. There are 419 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF408	NM_024741.3	c.52+36G>C		intron_variant	Intron 1 of 4	ENST00000311764.3	NP_079017.1
ZNF408	NM_001184751.2	c.22G>C	p.Gly8Arg	missense_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.52+36G>C		intron_variant	Intron 1 of 4	1	NM_024741.3	ENSP00000309606.2
ZNF408	ENST00000526410.1	n.69+36G>C		intron_variant	Intron 1 of 2	3
ZNF408	ENST00000531866.1	n.70+36G>C		intron_variant	Intron 1 of 1	2
ZNF408	ENST00000534481.1	n.-73G>C		upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.00576 AC: 876 AN: 152170 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00333 AC: 830 AN: 248886 Hom.: 1 AF XY: 0.00324 AC XY: 437 AN XY: 134810

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0183

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00316

Gnomad NFE exome AF: 0.00224

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00304 AC: 4445 AN: 1461640 Hom.: 16 Cov.: 31 AF XY: 0.00300 AC XY: 2182 AN XY: 727124

Gnomad4 AFR exome AF: 0.0155

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.0171

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00225

Gnomad4 NFE exome AF: 0.00264

Gnomad4 OTH exome AF: 0.00460

GnomAD4 genome AF: 0.00577 AC: 878 AN: 152288 Hom.: 9 Cov.: 33 AF XY: 0.00563 AC XY: 419 AN XY: 74476

Gnomad4 AFR AF: 0.0135

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00332 Hom.: 4

Bravo AF: 0.00574

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.1
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs111794632; hg19: chr11-46722685;