19-57357269-T-G

Variant names:

• chr19-57357269-T-G
• rs193920881
• NM_020657.4:c.1400T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020657.4(ZNF304):​c.1400T>G​(p.Ile467Arg) 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. 15/22 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. I467K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 34)
  • Failed GnomAD Quality Control
• Consequence: ZNF304 NM_020657.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.683
• Publications: 0 publications found

Genes affected

ZNF304 (HGNC:13505): (zinc finger protein 304) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein functions as a transcriptional repressor that recruits a corepressor complex to stimulate promoter hypermethylation and transcriptional silencing of target genes. Expression of this gene is upregulated in colorectal, ovarian and breast cancer, and this gene may promote cancer cell survival, growth and invasion. [provided by RefSeq, Jul 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037388176).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020657.4. 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
	ZNF304	NM_020657.4	MANE Select	c.1400T>G	p.Ile467Arg	missense	Exon 3 of 3	NP_065708.2	Q9HCX3
	ZNF304	NM_001290318.2		c.1541T>G	p.Ile514Arg	missense	Exon 4 of 4	NP_001277247.1	E7EQD3
	ZNF304	NM_001290319.2		c.1274T>G	p.Ile425Arg	missense	Exon 4 of 4	NP_001277248.1	M0QZ59

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF304	ENST00000282286.6	TSL:2 MANE Select	c.1400T>G	p.Ile467Arg	missense	Exon 3 of 3	ENSP00000282286.4	Q9HCX3
	ZNF304	ENST00000443917.6	TSL:1	c.1541T>G	p.Ile514Arg	missense	Exon 4 of 4	ENSP00000401642.2	E7EQD3
	ZNF304	ENST00000598744.1	TSL:1	c.1274T>G	p.Ile425Arg	missense	Exon 4 of 4	ENSP00000470319.1	M0QZ59

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147552 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000208

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000150

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 36

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000135 AC: 2 AN: 147688 Hom.: 0 Cov.: 34 AF XY: 0.0000277 AC XY: 2 AN XY: 72112

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

African (AFR) AF: 0.00 AC: 0 AN: 39896

American (AMR) AF: 0.00 AC: 0 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3426

East Asian (EAS) AF: 0.000208 AC: 1 AN: 4802

South Asian (SAS) AF: 0.00 AC: 0 AN: 4630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000150 AC: 1 AN: 66632

Other (OTH) AF: 0.00 AC: 0 AN: 2032

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	12
DANN	Benign	0.90
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.8	N
PhyloP100		-0.68
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	4.4	N
REVEL	Benign	0.093
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.28
MutPred		0.52		Gain of disorder (P = 0.0286)
MVP		0.36
MPC		1.2
ClinPred		0.14	T
GERP RS		0.47
Varity_R		0.077
gMVP		0.27
Mutation Taster		=94/6	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: rs193920881; hg19: chr19-57868637;