18-74631025-G-A

Variant names:

• chr18-74631025-G-A
• rs779490722
• NM_017757.3:c.6G>A

Variant summary

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

The NM_017757.3(ZNF407):​c.6G>A​(p.Met2Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000344 in 1,455,276 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF407 NM_017757.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.92
• Publications: 1 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.6G>A	p.Met2Ile	missense	Exon 2 of 9	NP_060227.2	Q9C0G0-1
	ZNF407	NM_001384475.1		c.6G>A	p.Met2Ile	missense	Exon 2 of 9	NP_001371404.1	Q9C0G0-1
	ZNF407	NM_001146189.1		c.6G>A	p.Met2Ile	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.6G>A	p.Met2Ile	missense	Exon 2 of 9	ENSP00000299687.4	Q9C0G0-1
	ZNF407	ENST00000577538.5	TSL:2	c.6G>A	p.Met2Ile	missense	Exon 1 of 7	ENSP00000463270.1	Q9C0G0-2
	ZNF407	ENST00000949102.1		c.6G>A	p.Met2Ile	missense	Exon 2 of 9	ENSP00000619161.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000822 AC: 2 AN: 243168 AF XY: 0.00

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: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455276 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 723658

African (AFR) AF: 0.00 AC: 0 AN: 33140

American (AMR) AF: 0.00 AC: 0 AN: 43984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25876

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 85354

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109592

Other (OTH) AF: 0.00 AC: 0 AN: 60130

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

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	Pathogenic	0.74
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.86
MutPred		0.23		Gain of catalytic residue at M2 (P = 0.0497)
MVP		0.43
MPC		0.47
ClinPred		0.80	D
GERP RS		5.1
PromoterAI		-0.021	Neutral
Varity_R		0.63
gMVP		0.041
Mutation Taster		=91/9	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: rs779490722; hg19: chr18-72342981;