rs4297419

Variant names:

• chr11-46702739-C-G
• rs4297419
• NM_024741.3:c.366C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-46702739-C-G
• chr11-46702739-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024741.3(ZNF408):​c.366C>G​(p.Ala122Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,614,084 control chromosomes in the GnomAD database, including 3,814 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (1902 hom., cov: 33)
  • Exomes 𝑓: 0.0091 (1912 hom.)
• Consequence: ZNF408 NM_024741.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.890
• Publications: 3 publications found

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-46702739-C-G is Benign according to our data. Variant chr11-46702739-C-G is described in ClinVar as Benign. ClinVar VariationId is 261759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024741.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF408	NM_024741.3	MANE Select	c.366C>G	p.Ala122Ala	synonymous	Exon 3 of 5	NP_079017.1	Q9H9D4
	ZNF408	NM_001184751.2		c.342C>G	p.Ala114Ala	synonymous	Exon 3 of 5	NP_001171680.1	B4DXY4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF408	ENST00000311764.3	TSL:1 MANE Select	c.366C>G	p.Ala122Ala	synonymous	Exon 3 of 5	ENSP00000309606.2	Q9H9D4
	ZNF408	ENST00000877975.1		c.438C>G	p.Ala146Ala	synonymous	Exon 4 of 6	ENSP00000548034.1
	ZNF408	ENST00000526410.1	TSL:3	n.383C>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.0862 AC: 13111 AN: 152126 Hom.: 1893 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00227

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0666

GnomAD2 exomes AF: 0.0222 AC: 5588 AN: 251482 AF XY: 0.0165

Gnomad AFR exome AF: 0.304

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.00915 AC: 13373 AN: 1461840 Hom.: 1912 Cov.: 31 AF XY: 0.00786 AC XY: 5719 AN XY: 727212

African (AFR) AF: 0.323 AC: 10816 AN: 33454

American (AMR) AF: 0.0151 AC: 676 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00107 AC: 92 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5768

European-Non Finnish (NFE) AF: 0.000403 AC: 448 AN: 1112000

Other (OTH) AF: 0.0203 AC: 1223 AN: 60390

GnomAD4 genome AF: 0.0863 AC: 13145 AN: 152244 Hom.: 1902 Cov.: 33 AF XY: 0.0839 AC XY: 6244 AN XY: 74446

African (AFR) AF: 0.300 AC: 12468 AN: 41492

American (AMR) AF: 0.0297 AC: 454 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68038

Other (OTH) AF: 0.0659 AC: 139 AN: 2108

Alfa AF: 0.0250 Hom.: 170

Bravo AF: 0.0973

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.0
DANN	Benign	0.62
PhyloP100		-0.89
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs4297419; hg19: chr11-46724289;