Genetic Variant NM_021964.3:c.1913C>A (chr3-125232813-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_021964.3(ZNF148):c.1913C>A(p.Pro638Gln) 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 benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ZNF148
NM_021964.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.67

Publications

0 publications found

Variant links:

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]

ZNF148 Gene-Disease associations (from GenCC):

global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ZNF148 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-125232813-G-T is Pathogenic according to our data. Variant chr3-125232813-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1507969.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.1222775). . Strength limited to SUPPORTING due to the PP5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021964.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF148	NM_021964.3	MANE Select	c.1913C>A	p.Pro638Gln	missense	Exon 9 of 9	NP_068799.2	Q9UQR1-1
ZNF148	NM_001348424.1		c.1913C>A	p.Pro638Gln	missense	Exon 10 of 10	NP_001335353.1	Q9UQR1-1
ZNF148	NM_001348425.2		c.1913C>A	p.Pro638Gln	missense	Exon 10 of 10	NP_001335354.1	Q9UQR1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZNF148	ENST00000360647.9	TSL:1 MANE Select	c.1913C>A	p.Pro638Gln	missense	Exon 9 of 9	ENSP00000353863.4	Q9UQR1-1
ZNF148	ENST00000484491.5	TSL:1	c.1913C>A	p.Pro638Gln	missense	Exon 9 of 9	ENSP00000420335.1	Q9UQR1-1
ZNF148	ENST00000485866.5	TSL:1	c.1913C>A	p.Pro638Gln	missense	Exon 10 of 10	ENSP00000420448.1	Q9UQR1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.27

Eigen

Benign

0.077

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.010

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

7.7

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.85

REVEL

Benign

0.093

Sift

Uncertain

0.029

Sift4G

Benign

0.14

Polyphen

0.021

Vest4

0.14

MutPred

0.10

Loss of disorder (P = 0.2732)

MVP

0.18

MPC

0.74

ClinPred

0.80

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.26

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over