chr18-74634668-C-T

Variant names:

• chr18-74634668-C-T
• rs776425129
• NM_017757.3:c.3649C>T

Variant summary

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

The NM_017757.3(ZNF407):​c.3649C>T​(p.His1217Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF407 NM_017757.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.813
• Publications: 0 publications found

Genes affected

ZNF407 (HGNC:19904): (zinc finger protein 407) This gene encodes a zinc finger protein whose exact function is not known. It may be involved in transcriptional regulation. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZNF407 Gene-Disease associations (from GenCC):

• short stature, impaired intellectual development, microcephaly, hypotonia, and ocular anomalies

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• intellectual disability

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.092524916).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017757.3. 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
	ZNF407	NM_017757.3	MANE Select	c.3649C>T	p.His1217Tyr	missense	Exon 2 of 9	NP_060227.2	Q9C0G0-1
	ZNF407	NM_001384475.1		c.3649C>T	p.His1217Tyr	missense	Exon 2 of 9	NP_001371404.1	Q9C0G0-1
	ZNF407	NM_001146189.1		c.3649C>T	p.His1217Tyr	missense	Exon 1 of 7	NP_001139661.1	Q9C0G0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF407	ENST00000299687.10	TSL:1 MANE Select	c.3649C>T	p.His1217Tyr	missense	Exon 2 of 9	ENSP00000299687.4	Q9C0G0-1
	ZNF407	ENST00000577538.5	TSL:2	c.3649C>T	p.His1217Tyr	missense	Exon 1 of 7	ENSP00000463270.1	Q9C0G0-2
	ZNF407	ENST00000309902.10	TSL:2	c.3649C>T	p.His1217Tyr	missense	Exon 1 of 4	ENSP00000310359.5	Q9C0G0-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249084 AF XY: 0.00000740

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461674 Hom.: 0 Cov.: 41 AF XY: 0.00000275 AC XY: 2 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111868

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.81
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Uncertain	0.021	D
Sift4G	Benign	0.27	T
Polyphen		0.78	P
Vest4		0.23
MutPred		0.15		Loss of methylation at K1215 (P = 0.1025)
MVP		0.15
MPC		0.20
ClinPred		0.24	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.17
Mutation Taster		=96/4	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: rs776425129; hg19: chr18-72346624;