chr19-57397132-C-T

Variant names:

• chr19-57397132-C-T
• rs749209546
• NM_001172773.2:c.136C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001172773.2(ZNF548):​c.136C>T​(p.Arg46Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,612,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ZNF548 NM_001172773.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.49
• Publications: 1 publications found

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]

ENSG00000269533 (HGNC:):

ACMG classification

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=0.059394807).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001172773.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF548	NM_001172773.2	MANE Select	c.136C>T	p.Arg46Cys	missense	Exon 3 of 4	NP_001166244.1	Q8NEK5-2
	ZNF548	NM_152909.4		c.100C>T	p.Arg34Cys	missense	Exon 2 of 3	NP_690873.2	Q8NEK5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF548	ENST00000336128.12	TSL:2 MANE Select	c.136C>T	p.Arg46Cys	missense	Exon 3 of 4	ENSP00000337555.6	Q8NEK5-2
	ZNF548	ENST00000366197.10	TSL:1	c.100C>T	p.Arg34Cys	missense	Exon 2 of 3	ENSP00000379482.3	Q8NEK5-1
	ENSG00000269533	ENST00000596400.1	TSL:4	c.51+2909C>T		intron	N/A	ENSP00000472277.1	M0R233

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250610 AF XY: 0.00000738

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460754 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 726722

African (AFR) AF: 0.0000598 AC: 2 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111402

Other (OTH) AF: 0.0000166 AC: 1 AN: 60316

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74240

African (AFR) AF: 0.0000967 AC: 4 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000548

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.024	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.059	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-2.5
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.083
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.0010	B
Vest4		0.081
MVP		0.27
MPC		0.19
ClinPred		0.054	T
GERP RS		-3.7
Varity_R		0.12
gMVP		0.39
Mutation Taster		=97/3	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

Other links and lift over

dbSNP: rs749209546; hg19: chr19-57908500; COSMIC: COSV105905836;