chr19-12349837-C-T

Variant names:

• chr19-12349837-C-T
• rs765612522
• NM_030824.3:c.1748G>A

Variant summary

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

The NM_030824.3(ZNF442):​c.1748G>A​(p.Arg583His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,608,234 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R583C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: ZNF442 NM_030824.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.76
• Publications: 2 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: 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=0.05427769).

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.1748G>A	p.Arg583His	missense	Exon 6 of 6	NP_110451.1	Q9H7R0-1
	ZNF442	NM_001363774.2		c.1541G>A	p.Arg514His	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.1748G>A	p.Arg583His	missense	Exon 6 of 6	ENSP00000242804.4	Q9H7R0-1
	ZNF442	ENST00000545749.2	TSL:5	c.1748G>A	p.Arg583His	missense	Exon 4 of 4	ENSP00000440162.2	Q9H7R0-1
	ZNF442	ENST00000438182.5	TSL:2	c.1541G>A	p.Arg514His	missense	Exon 3 of 3	ENSP00000388634.1	Q9H7R0-2

Frequencies

GnomAD3 genomes AF: 0.0000202 AC: 3 AN: 148324 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000747

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251248 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1459910 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726208

African (AFR) AF: 0.0000299 AC: 1 AN: 33426

American (AMR) AF: 0.0000225 AC: 1 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39614

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85878

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111022

Other (OTH) AF: 0.00 AC: 0 AN: 60288

GnomAD4 genome AF: 0.0000202 AC: 3 AN: 148324 Hom.: 0 Cov.: 32 AF XY: 0.0000415 AC XY: 3 AN XY: 72372

African (AFR) AF: 0.0000747 AC: 3 AN: 40142

American (AMR) AF: 0.00 AC: 0 AN: 14950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3420

East Asian (EAS) AF: 0.00 AC: 0 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66804

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

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	Benign	0.19
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.75
DEOGEN2	Benign	0.0018	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.000010	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L
PhyloP100		-2.8
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.011
Sift	Benign	0.55	T
Sift4G	Benign	0.66	T
Polyphen		0.036	B
Vest4		0.060
MVP		0.15
MPC		0.074
ClinPred		0.023	T
GERP RS		-1.6
Varity_R		0.018
gMVP		0.028
Mutation Taster		=100/0	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: rs765612522; hg19: chr19-12460651; COSMIC: COSV54420529; COSMIC: COSV54420529;