Genetic Variant ZNF548:p.Asn115Ser (chr19-57398595-A-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_001172773.2(ZNF548):c.344A>G(p.Asn115Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ZNF548
NM_001172773.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -7.67

Variant links:

Genes affected

ZNF548 (HGNC:26561): (zinc finger protein 548) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF548 links:

ENSG00000269533 (HGNC:):

ENSG00000269533 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.059140533).

BP6

Variant 19-57398595-A-G is Benign according to our data. Variant chr19-57398595-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2217595.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF548	NM_001172773.2 link	c.344A>G	p.Asn115Ser	missense_variant	Exon 4 of 4	ENST00000336128.12	NP_001166244.1	Q8NEK5-2
ZNF548	NM_152909.4 link	c.308A>G	p.Asn103Ser	missense_variant	Exon 3 of 3		NP_690873.2	Q8NEK5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF548	ENST00000336128.12 link	c.344A>G	p.Asn115Ser	missense_variant	Exon 4 of 4	2	NM_001172773.2	ENSP00000337555.6	Q8NEK5-2
ENSG00000269533	ENST00000596400.1 link	c.51+4372A>G		intron_variant	Intron 2 of 3	4		ENSP00000472277.1	M0R233
ENSG00000268533	ENST00000597410.1 link	c.39+4372A>G		intron_variant	Intron 1 of 2	3		ENSP00000472152.1	M0R1W7
ENSG00000268133	ENST00000597658.1 link	c.*11A>G		downstream_gene_variant		3		ENSP00000472894.1	M0R2Z0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727138

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 13, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.0040

DANN

Benign

0.37

DEOGEN2

Benign

0.0051

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.024

T;T;T

M_CAP

Benign

0.00068

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.14

N;.;.

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.75

N;N;.

REVEL

Benign

0.071

Sift

Benign

0.17

T;T;.

Sift4G

Benign

0.10

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.0060

MVP

0.17

MPC

0.11

ClinPred

0.31

GERP RS

-5.7

Varity_R

0.014

gMVP

0.077

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over