chr18-74881076-C-G

Variant names:

• chr18-74881076-C-G
• rs34940122
• NM_017757.3:c.5085C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_017757.3(ZNF407):​c.5085C>G​(p.Gly1695Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000225 in 1,556,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: ZNF407 NM_017757.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.265
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 18-74881076-C-G is Benign according to our data. Variant chr18-74881076-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 212672.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.265 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF407	NM_017757.3	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 6 of 9	ENST00000299687.10	NP_060227.2
ZNF407	NM_001384475.1	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 6 of 9		NP_001371404.1
ZNF407	NM_001146189.1	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 5 of 7		NP_001139661.1
ZNF407	XM_017025838.3	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 6 of 8		XP_016881327.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF407	ENST00000299687.10	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 6 of 9	1	NM_017757.3	ENSP00000299687.4
ZNF407	ENST00000577538.5	c.5085C>G	p.Gly1695Gly	synonymous_variant	Exon 5 of 7	2		ENSP00000463270.1
ZNF407	ENST00000581829.2	c.198C>G	p.Gly66Gly	synonymous_variant	Exon 2 of 4	5		ENSP00000479246.1
ZNF407	ENST00000584235.5	c.207C>G	p.Gly69Gly	synonymous_variant	Exon 2 of 4	3		ENSP00000481798.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152014 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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000300 AC: 49 AN: 163360 AF XY: 0.000261

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000347

Gnomad EAS exome AF: 0.000242

Gnomad FIN exome AF: 0.00225

Gnomad NFE exome AF: 0.000240

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000235 AC: 33 AN: 1404900 Hom.: 0 Cov.: 31 AF XY: 0.0000274 AC XY: 19 AN XY: 694472

⚠️ 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: 32090

American (AMR) AF: 0.00 AC: 0 AN: 37502

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25274

East Asian (EAS) AF: 0.0000274 AC: 1 AN: 36554

South Asian (SAS) AF: 0.00 AC: 0 AN: 80462

European-Finnish (FIN) AF: 0.000331 AC: 15 AN: 45310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1083920

Other (OTH) AF: 0.0000172 AC: 1 AN: 58254

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000158984), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152014 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74248

African (AFR) AF: 0.00 AC: 0 AN: 41420

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67904

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 23, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	2.3
DANN	Benign	0.80
PhyloP100		-0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs34940122; hg19: chr18-72593032;