19-43607922-G-A

Variant names:

• chr19-43607922-G-A
• rs1161566069
• NM_182498.4:c.262C>T

Variant summary

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

The NM_182498.4(ZNF428):​c.262C>T​(p.Pro88Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,420,780 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. P88T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZNF428 NM_182498.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

Genes affected

ZNF428 (HGNC:20804): (zinc finger protein 428) Predicted to enable metal ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

SRRM5 (HGNC:37248): (serine/arginine repetitive matrix 5)

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=0.32198116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182498.4. 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
	ZNF428	NM_182498.4	MANE Select	c.262C>T	p.Pro88Ser	missense	Exon 3 of 3	NP_872304.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF428	ENST00000300811.8	TSL:1 MANE Select	c.262C>T	p.Pro88Ser	missense	Exon 3 of 3	ENSP00000300811.2	Q96B54
	ZNF428	ENST00000855579.1		c.361C>T	p.Pro121Ser	missense	Exon 4 of 4	ENSP00000525638.1
	ZNF428	ENST00000855581.1		c.361C>T	p.Pro121Ser	missense	Exon 5 of 5	ENSP00000525640.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1420780 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 703446

⚠️ 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: 32660

American (AMR) AF: 0.00 AC: 0 AN: 37318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25346

East Asian (EAS) AF: 0.00 AC: 0 AN: 37544

South Asian (SAS) AF: 0.00 AC: 0 AN: 82554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5642

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1091250

Other (OTH) AF: 0.00 AC: 0 AN: 58896

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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	0.14
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.0
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-8.0	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.20	T
Polyphen		0.97	D
Vest4		0.27
MutPred		0.37		Loss of catalytic residue at P88 (P = 0.0013)
MVP		0.26
MPC		0.55
ClinPred		0.97	D
GERP RS		3.7
Varity_R		0.83
gMVP		0.68
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: rs1161566069; hg19: chr19-44112074;