19-56158596-C-G

Variant names:

• chr19-56158596-C-G
• NM_018337.4:c.400C>G

Variant summary

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

The NM_018337.4(ZNF444):​c.400C>G​(p.Pro134Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF444 NM_018337.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.249

Genes affected

ZNF444 (HGNC:16052): (zinc finger protein 444) This gene encodes a zinc finger protein which activates transcription of a scavenger receptor gene involved in the degradation of acetylated low density lipoprotein (Ac-LDL) (PMID: 11978792). This gene is located in a cluster of zinc finger genes on chromosome 19 at q13.4. A pseudogene of this gene is located on chromosome 15. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

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=0.19593334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF444	NM_018337.4	c.400C>G	p.Pro134Ala	missense_variant	Exon 4 of 5	ENST00000337080.8	NP_060807.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF444	ENST00000337080.8	c.400C>G	p.Pro134Ala	missense_variant	Exon 4 of 5	1	NM_018337.4	ENSP00000338860.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455440 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.400C>G (p.P134A) alteration is located in exon 4 (coding exon 2) of the ZNF444 gene. This alteration results from a C to G substitution at nucleotide position 400, causing the proline (P) at amino acid position 134 to be replaced by an alanine (A). 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	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.9	N;.
REVEL	Benign	0.059
Sift	Benign	0.40	T;.
Sift4G	Benign	0.29	T;T
Polyphen		0.99	D;D
Vest4		0.35
MutPred		0.24		Loss of phosphorylation at S130 (P = 0.2256);Loss of phosphorylation at S130 (P = 0.2256);
MVP		0.43
MPC		1.8
ClinPred		0.32	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.37

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: chr19-56669965;