NM_001172773.2:c.1603A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001172773.2(ZNF548):​c.1603A>G​(p.Ile535Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,607,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ZNF548
NM_001172773.2 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.237

Publications

0 publications found
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.042257667).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ZNF548NM_001172773.2 linkc.1603A>G p.Ile535Val missense_variant Exon 4 of 4 ENST00000336128.12 NP_001166244.1 Q8NEK5-2
ZNF548NM_152909.4 linkc.1567A>G p.Ile523Val missense_variant Exon 3 of 3 NP_690873.2 Q8NEK5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ZNF548ENST00000336128.12 linkc.1603A>G p.Ile535Val missense_variant Exon 4 of 4 2 NM_001172773.2 ENSP00000337555.6 Q8NEK5-2
ENSG00000269533ENST00000596400.1 linkc.51+5631A>G intron_variant Intron 2 of 3 4 ENSP00000472277.1 M0R233
ENSG00000268533ENST00000597410.1 linkc.39+5631A>G intron_variant Intron 1 of 2 3 ENSP00000472152.1 M0R1W7

Frequencies

GnomAD3 genomes
AF:
0.0000328
AC:
5
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000123
AC:
3
AN:
244444
AF XY:
0.0000151
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000298
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000181
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000137
AC:
20
AN:
1454672
Hom.:
0
Cov.:
33
AF XY:
0.0000125
AC XY:
9
AN XY:
722354
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33284
American (AMR)
AF:
0.0000227
AC:
1
AN:
44072
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25960
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39530
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85890
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53292
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.0000172
AC:
19
AN:
1106816
Other (OTH)
AF:
0.00
AC:
0
AN:
60078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
1
3
4
6
7
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152356
Hom.:
0
Cov.:
33
AF XY:
0.0000268
AC XY:
2
AN XY:
74516
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41582
American (AMR)
AF:
0.000131
AC:
2
AN:
15304
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4832
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10632
Middle Eastern (MID)
AF:
0.00340
AC:
1
AN:
294
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.0000248
AC:
3

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 26, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1603A>G (p.I535V) alteration is located in exon 4 (coding exon 4) of the ZNF548 gene. This alteration results from a A to G substitution at nucleotide position 1603, causing the isoleucine (I) at amino acid position 535 to be replaced by a valine (V). 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
Benign
0.074
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
0.14
DANN
Benign
0.41
DEOGEN2
Benign
0.0011
T;.
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.032
N
LIST_S2
Benign
0.20
T;T
M_CAP
Benign
0.0013
T
MetaRNN
Benign
0.042
T;T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.63
N;.
PhyloP100
0.24
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.25
N;N
REVEL
Benign
0.074
Sift
Benign
0.55
T;T
Sift4G
Benign
0.52
T;T
Polyphen
0.012
B;B
Vest4
0.056
MVP
0.12
MPC
0.12
ClinPred
0.021
T
GERP RS
-1.3
Varity_R
0.014
gMVP
0.042
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs377618513; hg19: chr19-57911222; API