3-125232607-C-A

Position:

• chr3-125232607-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_021964.3(ZNF148):​c.2119G>T​(p.Asp707Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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: 5.85

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
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ZNF148. . Gene score misZ 3.5168 (greater than the threshold 3.09). Trascript score misZ 4.5786 (greater than threshold 3.09). GenCC has associacion of gene with global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2810223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF148	NM_021964.3	c.2119G>T	p.Asp707Tyr	missense_variant	9/9	ENST00000360647.9	NP_068799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF148	ENST00000360647.9	c.2119G>T	p.Asp707Tyr	missense_variant	9/9	1	NM_021964.3	ENSP00000353863	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 75

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 04, 2024

The c.2119G>T (p.D707Y) alteration is located in exon 9 (coding exon 6) of the ZNF148 gene. This alteration results from a G to T substitution at nucleotide position 2119, causing the aspartic acid (D) at amino acid position 707 to be replaced by a tyrosine (Y). 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	0.73
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;T;D;D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;.;.;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.28	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.55	N;.;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.1	D;N;D;D;D
REVEL	Benign	0.26
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Uncertain	0.0020	D;T;D;D;D
Polyphen		0.52	P;P;P;P;P
Vest4		0.42
MutPred		0.34		Loss of disorder (P = 0.0245);.;Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);Loss of disorder (P = 0.0245);
MVP		0.38
MPC		1.8
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.66
gMVP		0.71

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

LitVar

Other links and lift over

dbSNP: rs1935903715; hg19: chr3-124951451;