chr19-50041738-A-G

Variant names:

• chr19-50041738-A-G
• rs1978783490
• NM_015428.4:c.145A>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.145A>G​(p.Arg49Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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)
• Consequence: ZNF473 NM_015428.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• 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]

ENSG00000298681 (HGNC:):

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=0.08590919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF473	NM_015428.4	c.145A>G	p.Arg49Gly	missense_variant	Exon 4 of 5	ENST00000270617.8	NP_056243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF473	ENST00000270617.8	c.145A>G	p.Arg49Gly	missense_variant	Exon 4 of 5	1	NM_015428.4	ENSP00000270617.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.145A>G (p.R49G) alteration is located in exon 4 (coding exon 3) of the ZNF473 gene. This alteration results from a A to G substitution at nucleotide position 145, causing the arginine (R) at amino acid position 49 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0089	.;T;T;T;.;.;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.61	T;.;.;T;T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.086	T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	.;L;L;L;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.9	.;.;D;D;D;.;.
REVEL	Benign	0.023
Sift	Uncertain	0.010	.;.;D;D;D;.;.
Sift4G	Uncertain	0.054	T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.;.;.
Vest4		0.15, 0.13, 0.13, 0.14
MutPred		0.33		Gain of glycosylation at P50 (P = 0.1227);Gain of glycosylation at P50 (P = 0.1227);Gain of glycosylation at P50 (P = 0.1227);Gain of glycosylation at P50 (P = 0.1227);.;Gain of glycosylation at P50 (P = 0.1227);Gain of glycosylation at P50 (P = 0.1227);
MVP		0.15
MPC		0.38
ClinPred		0.11	T
GERP RS		1.5
Varity_R		0.12
gMVP		0.14
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1978783490; hg19: chr19-50544995;