3-125232934-T-C

Variant names:

• chr3-125232934-T-C
• NM_021964.3:c.1792A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_021964.3(ZNF148):​c.1792A>G​(p.Lys598Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF148 NM_021964.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

Genes affected

ZNF148 (HGNC:12933): (zinc finger protein 148) The protein encoded by this gene is a member of the Kruppel family of zinc finger DNA binding proteins. The encoded protein activates transcription of the T-cell receptor and intestinal alkaline phosphatase genes but represses transcription of the ornithine decarboxylase, vimentin, gastrin, stomelysin, and enolase genes. Increased expression of this gene results in decreased patient survival rates from colorectal cancer, while mutations in this gene have been associated with global developmental delay, hypoplastic corpus callosum, and dysmorphic facies. [provided by RefSeq, Feb 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF148	NM_021964.3	c.1792A>G	p.Lys598Glu	missense_variant	Exon 9 of 9	ENST00000360647.9	NP_068799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF148	ENST00000360647.9	c.1792A>G	p.Lys598Glu	missense_variant	Exon 9 of 9	1	NM_021964.3	ENSP00000353863.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 76

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1792A>G (p.K598E) alteration is located in exon 9 (coding exon 6) of the ZNF148 gene. This alteration results from a A to G substitution at nucleotide position 1792, causing the lysine (K) at amino acid position 598 to be replaced by a glutamic acid (E). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;D;D;D
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;.;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.7	M;M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.69
MutPred		0.31		Loss of ubiquitination at K598 (P = 0.0011);Loss of ubiquitination at K598 (P = 0.0011);Loss of ubiquitination at K598 (P = 0.0011);Loss of ubiquitination at K598 (P = 0.0011);
MVP		0.72
MPC		2.2
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.68

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: chr3-124951778;