19-12349852-C-A

Variant names:

• chr19-12349852-C-A
• rs371930767
• NM_030824.3:c.1733G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030824.3(ZNF442):​c.1733G>T​(p.Gly578Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. G578D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF442 NM_030824.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.31
• Publications: 0 publications found

Genes affected

ZNF442 (HGNC:20877): (zinc finger protein 442) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39598036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030824.3. 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
	ZNF442	NM_030824.3	MANE Select	c.1733G>T	p.Gly578Val	missense	Exon 6 of 6	NP_110451.1	Q9H7R0-1
	ZNF442	NM_001363774.2		c.1526G>T	p.Gly509Val	missense	Exon 3 of 3	NP_001350703.1	Q9H7R0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF442	ENST00000242804.9	TSL:2 MANE Select	c.1733G>T	p.Gly578Val	missense	Exon 6 of 6	ENSP00000242804.4	Q9H7R0-1
	ZNF442	ENST00000545749.2	TSL:5	c.1733G>T	p.Gly578Val	missense	Exon 4 of 4	ENSP00000440162.2	Q9H7R0-1
	ZNF442	ENST00000438182.5	TSL:2	c.1526G>T	p.Gly509Val	missense	Exon 3 of 3	ENSP00000388634.1	Q9H7R0-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	T
Eigen	Benign	0.090
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.56		Loss of disorder (P = 0.0378)
MVP		0.54
MPC		0.42
ClinPred		0.97	D
GERP RS		0.79
Varity_R		0.48
gMVP		0.030
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: rs371930767; hg19: chr19-12460666;