chr18-75063798-A-G

Variant names:

• chr18-75063798-A-G
• rs202203566
• NM_017757.3:c.6077A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_017757.3(ZNF407):​c.6077A>G​(p.Gln2026Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000993 in 1,609,040 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: ZNF407 NM_017757.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.139
• Publications: 3 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

ENSG00000278607 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012239844).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.6077A>G	p.Gln2026Arg	missense	Exon 9 of 9	NP_060227.2
	ZNF407	NM_001384475.1		c.6077A>G	p.Gln2026Arg	missense	Exon 9 of 9	NP_001371404.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF407	ENST00000299687.10	TSL:1 MANE Select	c.6077A>G	p.Gln2026Arg	missense	Exon 9 of 9	ENSP00000299687.4
	ZNF407	ENST00000949102.1		c.4433A>G	p.Gln1478Arg	missense	Exon 9 of 9	ENSP00000619161.1
	ZNF407	ENST00000949101.1		c.1487A>G	p.Gln496Arg	missense	Exon 9 of 9	ENSP00000619160.1

Frequencies

GnomAD3 genomes AF: 0.000790 AC: 120 AN: 151974 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.00127

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000624 AC: 152 AN: 243740 AF XY: 0.000639

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000639

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000158

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.00101 AC: 1477 AN: 1456950 Hom.: 3 Cov.: 29 AF XY: 0.000993 AC XY: 720 AN XY: 724950

African (AFR) AF: 0.000149 AC: 5 AN: 33476

American (AMR) AF: 0.000671 AC: 30 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.000225 AC: 11 AN: 48934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00125 AC: 1391 AN: 1111692

Other (OTH) AF: 0.000663 AC: 40 AN: 60334

GnomAD4 genome AF: 0.000789 AC: 120 AN: 152090 Hom.: 0 Cov.: 32 AF XY: 0.000753 AC XY: 56 AN XY: 74340

African (AFR) AF: 0.000169 AC: 7 AN: 41502

American (AMR) AF: 0.00150 AC: 23 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00127 AC: 86 AN: 67974

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000947 Hom.: 1

Bravo AF: 0.000801

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000957 AC: 8

ExAC AF: 0.000620 AC: 75

EpiCase AF: 0.000872

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.91
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.14
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.028
Sift	Benign	0.43	T
Sift4G	Benign	0.39	T
Polyphen		0.011	B
Vest4		0.16
MVP		0.17
MPC		0.20
ClinPred		0.015	T
GERP RS		0.86
Varity_R		0.060
gMVP		0.13
Mutation Taster		=99/1	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: rs202203566; hg19: chr18-72775754;