NM_001001415.4:c.185C>A

Variant names:

• chr19-21530643-C-A
• rs375122896
• NM_001001415.4:c.185C>A

Variant summary

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

The NM_001001415.4(ZNF429):​c.185C>A​(p.Pro62His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,459,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P62L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ZNF429 NM_001001415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.395
• Publications: 0 publications found

Genes affected

ZNF429 (HGNC:20817): (zinc finger protein 429) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2070359).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001415.4. 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
	ZNF429	NM_001001415.4	MANE Select	c.185C>A	p.Pro62His	missense	Exon 3 of 4	NP_001001415.2	Q86V71
	ZNF429	NM_001346912.2		c.179C>A	p.Pro60His	missense	Exon 3 of 4	NP_001333841.1
	ZNF429	NM_001346913.2		c.89C>A	p.Pro30His	missense	Exon 4 of 5	NP_001333842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF429	ENST00000358491.9	TSL:3 MANE Select	c.185C>A	p.Pro62His	missense	Exon 3 of 4	ENSP00000351280.3	Q86V71
	ZNF429	ENST00000597078.5	TSL:1	c.185C>A	p.Pro62His	missense	Exon 3 of 6	ENSP00000470300.1	M0QZ47
	ZNF429	ENST00000967842.1		c.146C>A	p.Pro49His	missense	Exon 3 of 4	ENSP00000637901.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459670 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726256

⚠️ 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: 33382

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 85922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110774

Other (OTH) AF: 0.00 AC: 0 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00455694), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

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	0.20
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-0.40
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.031
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.14
MutPred		0.36		Loss of catalytic residue at P62 (P = 0.0029)
MVP		0.58
MPC		0.21
ClinPred		0.98	D
GERP RS		0.23
Varity_R		0.31
gMVP		0.028
Mutation Taster		=85/15	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: rs375122896; hg19: chr19-21713445;