chr18-74781491-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_017757.3(ZNF407):​c.4866C>A​(p.Thr1622Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T1622T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: ZNF407 NM_017757.3 synonymous
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.17).
• 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>A	p.Thr1622Thr	synonymous	Exon 4 of 9	NP_060227.2
	ZNF407	NM_001384475.1		c.4866C>A	p.Thr1622Thr	synonymous	Exon 4 of 9	NP_001371404.1
	ZNF407	NM_001146189.1		c.4866C>A	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>A	p.Thr1622Thr	synonymous	Exon 4 of 9	ENSP00000299687.4
	ZNF407	ENST00000577538.5	TSL:2	c.4866C>A	p.Thr1622Thr	synonymous	Exon 3 of 7	ENSP00000463270.1
	ZNF407	ENST00000949102.1		c.3222C>A	p.Thr1074Thr	synonymous	Exon 4 of 9	ENSP00000619161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365962 Hom.: 0 Cov.: 29 AF XY: 0.00000148 AC XY: 1 AN XY: 673598

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000141 AC: 1 AN: 70790

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: 0.00 AC: 0 AN: 1067362

Other (OTH) AF: 0.00 AC: 0 AN: 56400

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.17
CADD	Benign	5.3
DANN	Benign	0.76
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;