3-125232870-T-C

Variant names:

• chr3-125232870-T-C
• rs1356948569
• NM_021964.3:c.1856A>G

Variant summary

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

The NM_021964.3(ZNF148):​c.1856A>G​(p.Asn619Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF148	NM_021964.3	c.1856A>G	p.Asn619Ser	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.1856A>G	p.Asn619Ser	missense_variant	Exon 9 of 9	1	NM_021964.3	ENSP00000353863.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 75

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000843 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 28, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	23
DANN	Benign	0.92
DEOGEN2	Benign	0.24	T;T;T;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	.;.;.;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.50	D;D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.91	L;L;L;L
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.47	N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.44	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.99	D;D;D;D
Vest4		0.62
MutPred		0.095		Gain of glycosylation at Y622 (P = 0.0116);Gain of glycosylation at Y622 (P = 0.0116);Gain of glycosylation at Y622 (P = 0.0116);Gain of glycosylation at Y622 (P = 0.0116);
MVP		0.61
MPC		1.7
ClinPred		0.65	D
GERP RS		4.7
Varity_R		0.087
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1356948569; hg19: chr3-124951714; COSMIC: COSV62303627;