chr18-74781491-C-T

Variant names:

• chr18-74781491-C-T
• rs752545983
• NM_017757.3:c.4866C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_017757.3(ZNF407):​c.4866C>T​(p.Thr1622Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000567 in 1,517,594 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (1 hom.)
• Consequence: ZNF407 NM_017757.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.306
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP7: Synonymous conserved (PhyloP=0.306 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF407	NM_017757.3	MANE Select	c.4866C>T	p.Thr1622Thr	synonymous	Exon 4 of 9	NP_060227.2
	ZNF407	NM_001384475.1		c.4866C>T	p.Thr1622Thr	synonymous	Exon 4 of 9	NP_001371404.1
	ZNF407	NM_001146189.1		c.4866C>T	p.Thr1622Thr	synonymous	Exon 3 of 7	NP_001139661.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF407	ENST00000299687.10	TSL:1 MANE Select	c.4866C>T	p.Thr1622Thr	synonymous	Exon 4 of 9	ENSP00000299687.4
	ZNF407	ENST00000577538.5	TSL:2	c.4866C>T	p.Thr1622Thr	synonymous	Exon 3 of 7	ENSP00000463270.1
	ZNF407	ENST00000949102.1		c.3222C>T	p.Thr1074Thr	synonymous	Exon 4 of 9	ENSP00000619161.1

Frequencies

GnomAD3 genomes AF: 0.0000330 AC: 5 AN: 151632 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000451 AC: 6 AN: 132994 AF XY: 0.0000565

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000576

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000899

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000593 AC: 81 AN: 1365962 Hom.: 1 Cov.: 29 AF XY: 0.0000594 AC XY: 40 AN XY: 673598

African (AFR) AF: 0.00 AC: 0 AN: 29252

American (AMR) AF: 0.0000690 AC: 2 AN: 29006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23780

East Asian (EAS) AF: 0.00 AC: 0 AN: 34674

South Asian (SAS) AF: 0.00 AC: 0 AN: 70792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.0000703 AC: 75 AN: 1067360

Other (OTH) AF: 0.0000709 AC: 4 AN: 56400

GnomAD4 genome AF: 0.0000330 AC: 5 AN: 151632 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74048

African (AFR) AF: 0.0000242 AC: 1 AN: 41264

American (AMR) AF: 0.00 AC: 0 AN: 15228

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

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

European-Non Finnish (NFE) AF: 0.0000589 AC: 4 AN: 67896

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000763 Hom.: 0

Bravo AF: 0.0000264

ClinVar

ClinVar submissions as Germline

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
BayesDel_noAF	Benign	-0.25
CADD	Benign	6.0
DANN	Benign	0.75
PhyloP100		0.31

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: rs752545983; hg19: chr18-72493447;