10-43556917-G-A

Variant names:

• chr10-43556917-G-A
• rs377453832
• NM_001099282.2:c.1163C>T

Variant summary

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

The NM_001099282.2(ZNF239):​c.1163C>T​(p.Ser388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,782 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. S388W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ZNF239 NM_001099282.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.631
• Publications: 0 publications found

Genes affected

ZNF239 (HGNC:13031): (zinc finger protein 239) MOK2 proteins are DNA- and RNA-binding proteins that are mainly associated with nuclear RNP components, including the nucleoli and extranucleolar structures (Arranz et al., 1997 [PubMed 9121460]).[supplied by OMIM, Mar 2008]

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=0.3834472).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099282.2. 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
	ZNF239	NM_001099282.2	MANE Select	c.1163C>T	p.Ser388Leu	missense	Exon 4 of 4	NP_001092752.1	Q16600
	ZNF239	NM_001324353.2		c.1502C>T	p.Ser501Leu	missense	Exon 5 of 5	NP_001311282.1
	ZNF239	NM_001324352.2		c.1289C>T	p.Ser430Leu	missense	Exon 4 of 4	NP_001311281.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF239	ENST00000374446.7	TSL:1 MANE Select	c.1163C>T	p.Ser388Leu	missense	Exon 4 of 4	ENSP00000363569.1	Q16600
	ZNF239	ENST00000306006.10	TSL:1	c.1163C>T	p.Ser388Leu	missense	Exon 2 of 2	ENSP00000307774.6	Q16600
	ZNF239	ENST00000426961.1	TSL:2	c.1163C>T	p.Ser388Leu	missense	Exon 3 of 3	ENSP00000398202.1	Q16600

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151928 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250310 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461854 Hom.: 0 Cov.: 30 AF XY: 0.00000963 AC XY: 7 AN XY: 727226

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111990

Other (OTH) AF: 0.0000331 AC: 2 AN: 60396

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151928 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74196

⚠️ 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: 41348

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ 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.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		0.63
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.14
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.60		Loss of disorder (P = 0.0186)
MVP		0.39
MPC		0.31
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.43
gMVP		0.024
Mutation Taster		=88/12	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: rs377453832; hg19: chr10-44052365;