14-102319827-C-T

Variant names:

• chr14-102319827-C-T
• rs2139438074
• NM_018335.6:c.62C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018335.6(ZNF839):​c.62C>T​(p.Pro21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,074,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 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. P21R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ZNF839 NM_018335.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.175
• Publications: 0 publications found

Genes affected

ZNF839 (HGNC:20345): (zinc finger protein 839) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1086801).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018335.6. 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
	ZNF839	NM_018335.6	MANE Select	c.62C>T	p.Pro21Leu	missense	Exon 1 of 8	NP_060805.3	A8K0R7-5
	ZNF839	NM_001385065.1		c.62C>T	p.Pro21Leu	missense	Exon 1 of 7	NP_001371994.1
	ZNF839	NM_001385072.1		c.62C>T	p.Pro21Leu	missense	Exon 1 of 8	NP_001372001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF839	ENST00000442396.7	TSL:5 MANE Select	c.62C>T	p.Pro21Leu	missense	Exon 1 of 8	ENSP00000399863.2	A8K0R7-5
	ZNF839	ENST00000892181.1		c.62C>T	p.Pro21Leu	missense	Exon 1 of 7	ENSP00000562240.1
	ZNF839	ENST00000892182.1		c.62C>T	p.Pro21Leu	missense	Exon 1 of 8	ENSP00000562241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000279 AC: 3 AN: 1074322 Hom.: 0 Cov.: 31 AF XY: 0.00000196 AC XY: 1 AN XY: 509168

⚠️ 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: 22456

American (AMR) AF: 0.00 AC: 0 AN: 8068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13744

East Asian (EAS) AF: 0.00 AC: 0 AN: 25776

South Asian (SAS) AF: 0.00 AC: 0 AN: 20582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2904

European-Non Finnish (NFE) AF: 0.00000327 AC: 3 AN: 917136

Other (OTH) AF: 0.00 AC: 0 AN: 42854

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000343967), 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	Benign	0.099
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	11
DANN	Benign	0.94
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.17
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.18	N
REVEL	Benign	0.057
Sift	Benign	0.086	T
Sift4G	Uncertain	0.017	D
Polyphen		0.90	P
Vest4		0.13
MutPred		0.32		Gain of catalytic residue at P21 (P = 0)
MVP		0.23
MPC		0.087
ClinPred		0.51	D
GERP RS		0.43
PromoterAI		0.17	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
gMVP		0.21
Mutation Taster		=93/7	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: rs2139438074; hg19: chr14-102786164;