18-74631060-A-T

Variant names:

• chr18-74631060-A-T
• rs762941748
• NM_017757.3:c.41A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017757.3(ZNF407):​c.41A>T​(p.Glu14Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E14G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF407 NM_017757.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.777
• 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: 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 (MetaRNN=0.06843111).

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.41A>T	p.Glu14Val	missense	Exon 2 of 9	NP_060227.2	Q9C0G0-1
	ZNF407	NM_001384475.1		c.41A>T	p.Glu14Val	missense	Exon 2 of 9	NP_001371404.1	Q9C0G0-1
	ZNF407	NM_001146189.1		c.41A>T	p.Glu14Val	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.41A>T	p.Glu14Val	missense	Exon 2 of 9	ENSP00000299687.4	Q9C0G0-1
	ZNF407	ENST00000577538.5	TSL:2	c.41A>T	p.Glu14Val	missense	Exon 1 of 7	ENSP00000463270.1	Q9C0G0-2
	ZNF407	ENST00000949102.1		c.41A>T	p.Glu14Val	missense	Exon 2 of 9	ENSP00000619161.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 58

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.78
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.019	D
Polyphen		0.82	P
Vest4		0.14
MutPred		0.10		Gain of methylation at K15 (P = 0.0424)
MVP		0.043
MPC		0.27
ClinPred		0.44	T
GERP RS		1.0
PromoterAI		-0.0078	Neutral
Varity_R		0.13
gMVP		0.12

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: rs762941748; hg19: chr18-72343016;