chr19-58478108-C-G

Position:

• chr19-58478108-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017908.4(ZNF446):​c.554C>G​(p.Ala185Gly) 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. 15/21 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: ZNF446 NM_017908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.339

Genes affected

ZNF446 (HGNC:21036): (zinc finger protein 446) Enables identical protein binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.085446954).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF446	NM_017908.4	c.554C>G	p.Ala185Gly	missense_variant	4/7	ENST00000594369.6	NP_060378.1
ZNF446	NM_001304453.1	c.554C>G	p.Ala185Gly	missense_variant	3/6		NP_001291382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF446	ENST00000594369.6	c.554C>G	p.Ala185Gly	missense_variant	4/7	1	NM_017908.4	ENSP00000472802	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2023

The c.554C>G (p.A185G) alteration is located in exon 4 (coding exon 3) of the ZNF446 gene. This alteration results from a C to G substitution at nucleotide position 554, causing the alanine (A) at amino acid position 185 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	0.11
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.5
DANN	Benign	0.84
DEOGEN2	Benign	0.011	T;T;.;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.67	T;T;T;T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.085	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.87	.;.;.;N;.
REVEL	Benign	0.015
Sift	Benign	0.37	.;.;.;T;.
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.13	.;B;.;.;.
Vest4		0.15
MutPred		0.20		Loss of glycosylation at P183 (P = 0.0895);Loss of glycosylation at P183 (P = 0.0895);Loss of glycosylation at P183 (P = 0.0895);Loss of glycosylation at P183 (P = 0.0895);Loss of glycosylation at P183 (P = 0.0895);
MVP		0.13
MPC		0.086
ClinPred		0.091	T
GERP RS		1.1
Varity_R		0.041
gMVP		0.14

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-58989475;