19-56158549-C-T

Variant names:

• chr19-56158549-C-T
• rs754371944
• NM_018337.4:c.353C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018337.4(ZNF444):​c.353C>T​(p.Thr118Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,611,908 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: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: ZNF444 NM_018337.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17120534).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018337.4. 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
	ZNF444	NM_018337.4	MANE Select	c.353C>T	p.Thr118Met	missense	Exon 4 of 5	NP_060807.2
	ZNF444	NM_001253792.2		c.353C>T	p.Thr118Met	missense	Exon 4 of 5	NP_001240721.1	Q8N0Y2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF444	ENST00000337080.8	TSL:1 MANE Select	c.353C>T	p.Thr118Met	missense	Exon 4 of 5	ENSP00000338860.3	Q8N0Y2-1
	ZNF444	ENST00000592949.5	TSL:1	c.353C>T	p.Thr118Met	missense	Exon 4 of 5	ENSP00000468069.1	Q8N0Y2-2
	ZNF444	ENST00000875359.1		c.353C>T	p.Thr118Met	missense	Exon 4 of 5	ENSP00000545418.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000362 AC: 9 AN: 248608 AF XY: 0.0000446

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1459788 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24 AN XY: 726214

African (AFR) AF: 0.0000300 AC: 1 AN: 33370

American (AMR) AF: 0.000359 AC: 16 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26046

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39426

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85922

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000252 AC: 28 AN: 1111030

Other (OTH) AF: 0.0000829 AC: 5 AN: 60304

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74302

African (AFR) AF: 0.0000483 AC: 2 AN: 41408

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

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	0.21
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.4
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.038
Sift	Benign	0.13	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.34
MVP		0.36
MPC		1.2
ClinPred		0.11	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.012
gMVP		0.45
Mutation Taster		=99/1	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: rs754371944; hg19: chr19-56669918; COSMIC: COSV108871133; COSMIC: COSV108871133;