19-57397169-C-T

Variant names:

• chr19-57397169-C-T
• NM_001172773.2:c.173C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001172773.2(ZNF548):​c.173C>T​(p.Ser58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF548 NM_001172773.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF548	NM_001172773.2	c.173C>T	p.Ser58Leu	missense_variant	Exon 3 of 4	ENST00000336128.12	NP_001166244.1
ZNF548	NM_152909.4	c.137C>T	p.Ser46Leu	missense_variant	Exon 2 of 3		NP_690873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF548	ENST00000336128.12	c.173C>T	p.Ser58Leu	missense_variant	Exon 3 of 4	2	NM_001172773.2	ENSP00000337555.6
ENSG00000269533	ENST00000596400.1	c.51+2946C>T		intron_variant	Intron 2 of 3	4		ENSP00000472277.1
ENSG00000268133	ENST00000597658.1	c.152-1261C>T		intron_variant	Intron 3 of 3	3		ENSP00000472894.1
ENSG00000268533	ENST00000597410.1	c.39+2946C>T		intron_variant	Intron 1 of 2	3		ENSP00000472152.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.173C>T (p.S58L) alteration is located in exon 3 (coding exon 3) of the ZNF548 gene. This alteration results from a C to T substitution at nucleotide position 173, causing the serine (S) at amino acid position 58 to be replaced by a leucine (L). 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	0.17
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.;.;.;.;.;.;.
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.65	T;T;T;T;T;T;D;T
M_CAP	Benign	0.0032	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.4	M;.;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Pathogenic	-4.9	D;.;.;.;D;.;.;.
REVEL	Benign	0.080
Sift	Uncertain	0.0010	D;.;.;.;D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;D;.;.;.
Vest4		0.73
MutPred		0.73		Loss of catalytic residue at S46 (P = 0.0107);.;.;.;.;.;.;.;
MVP		0.36
MPC		0.17
ClinPred		0.92	D
GERP RS		1.5
Varity_R		0.47
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-57908537; COSMIC: COSV100278278; COSMIC: COSV100278278;