19-11867670-A-C

Variant names:

• chr19-11867670-A-C
• rs772083513
• NM_001348719.2:c.616A>C

Variant summary

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

The NM_001348719.2(ZNF439):​c.616A>C​(p.Ile206Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,818 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. I206V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ZNF439 NM_001348719.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.825
• Publications: 0 publications found

Genes affected

ZNF439 (HGNC:20873): (zinc finger protein 439) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located 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=0.042892843).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001348719.2. 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
	ZNF439	NM_001348719.2	MANE Select	c.616A>C	p.Ile206Leu	missense	Exon 4 of 4	NP_001335648.1	A0A804HI69
	ZNF439	NM_001348718.2		c.625A>C	p.Ile209Leu	missense	Exon 4 of 4	NP_001335647.1
	ZNF439	NM_152262.3		c.601A>C	p.Ile201Leu	missense	Exon 3 of 3	NP_689475.1	Q8NDP4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF439	ENST00000682736.1	MANE Select	c.616A>C	p.Ile206Leu	missense	Exon 4 of 4	ENSP00000506930.1	A0A804HI69
	ZNF439	ENST00000304030.2	TSL:1	c.601A>C	p.Ile201Leu	missense	Exon 3 of 3	ENSP00000305077.2	Q8NDP4
	ZNF439	ENST00000455282.1	TSL:1	c.193A>C	p.Ile65Leu	missense	Exon 3 of 3	ENSP00000395632.1	A0A0C4DG37

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

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

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.027
DANN	Benign	0.21
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.044	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-3.0	N
PhyloP100		-0.82
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.077
MutPred		0.61		Gain of catalytic residue at I201 (P = 0.0953)
MVP		0.20
MPC		0.066
ClinPred		0.029	T
GERP RS		0.12
Varity_R		0.061
gMVP		0.013
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: rs772083513; hg19: chr19-11978485; COSMIC: COSV108856250; COSMIC: COSV108856250;