NM_024741.3:c.1850C>T

Variant names:

• chr11-46705550-C-T
• rs547169524
• NM_024741.3:c.1850C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_024741.3(ZNF408):​c.1850C>T​(p.Thr617Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000895 in 1,452,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T617N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ZNF408 NM_024741.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.107
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12819117).

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.1850C>T	p.Thr617Ile	missense	Exon 5 of 5	NP_079017.1	Q9H9D4
	ZNF408	NM_001184751.2		c.1826C>T	p.Thr609Ile	missense	Exon 5 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.1850C>T	p.Thr617Ile	missense	Exon 5 of 5	ENSP00000309606.2	Q9H9D4
	ZNF408	ENST00000877975.1		c.1922C>T	p.Thr641Ile	missense	Exon 6 of 6	ENSP00000548034.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000895 AC: 13 AN: 1452930 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 723228

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111938

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.11
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.036
Sift	Benign	0.14	T
Sift4G	Uncertain	0.047	D
Polyphen		0.67	P
Vest4		0.37
MutPred		0.36		Gain of catalytic residue at L622 (P = 0.0213)
MVP		0.11
MPC		0.56
ClinPred		0.46	T
GERP RS		3.4
Varity_R		0.062
gMVP		0.23
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs547169524; hg19: chr11-46727100;