19-50045149-C-G

Variant names:

• chr19-50045149-C-G
• rs1435223842
• NM_015428.4:c.706C>G

Variant summary

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

The NM_015428.4(ZNF473):​c.706C>G​(p.Pro236Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF473 NM_015428.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.797
• Publications: 0 publications found

Genes affected

ZNF473 (HGNC:23239): (zinc finger protein 473) This gene encodes a member of the Krueppel C2H2-type zinc-finger family of proteins. The encoded protein, a component of the U7 snRNP complex, plays a role in histone 3'-end pre-mRNA processing and may be required for cell cycle progression to S phase. Expression level and methylation status of this gene may be correlated with bone mineral density. [provided by RefSeq, Jul 2016]

ZNF473-AS1 (HGNC:58330):

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=0.16195181).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015428.4. 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
	ZNF473	NM_015428.4	MANE Select	c.706C>G	p.Pro236Ala	missense	Exon 5 of 5	NP_056243.1	Q8WTR7
	ZNF473	NM_001006656.4		c.706C>G	p.Pro236Ala	missense	Exon 5 of 5	NP_001006657.1	Q8WTR7
	ZNF473	NM_001308424.3		c.670C>G	p.Pro224Ala	missense	Exon 4 of 4	NP_001295353.1	F8WEC7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF473	ENST00000270617.8	TSL:1 MANE Select	c.706C>G	p.Pro236Ala	missense	Exon 5 of 5	ENSP00000270617.3	Q8WTR7
	ZNF473	ENST00000391821.6	TSL:1	c.706C>G	p.Pro236Ala	missense	Exon 5 of 5	ENSP00000375697.1	Q8WTR7
	ZNF473	ENST00000595661.5	TSL:5	c.706C>G	p.Pro236Ala	missense	Exon 6 of 6	ENSP00000472808.1	Q8WTR7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727248

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

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	0.15
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.80
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Benign	0.15
Sift	Benign	0.071	T
Sift4G	Uncertain	0.0080	D
Polyphen		0.25	B
Vest4		0.078
MutPred		0.40		Loss of catalytic residue at P236 (P = 0.0645)
MVP		0.51
MPC		0.80
ClinPred		0.90	D
GERP RS		0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.045
gMVP		0.045
Mutation Taster		=75/25	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: rs1435223842; hg19: chr19-50548406;