19-57399306-A-G

Variant names:

• chr19-57399306-A-G
• rs201989885
• NM_001172773.2:c.1055A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001172773.2(ZNF548):​c.1055A>G​(p.Asn352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,568 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: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: ZNF548 NM_001172773.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.97

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 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=0.0056828856).
• BP6: Variant 19-57399306-A-G is Benign according to our data. Variant chr19-57399306-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3821694.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	c.1055A>G	p.Asn352Ser	missense_variant	Exon 4 of 4	ENST00000336128.12	NP_001166244.1
ZNF548	NM_152909.4	c.1019A>G	p.Asn340Ser	missense_variant	Exon 3 of 3		NP_690873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF548	ENST00000336128.12	c.1055A>G	p.Asn352Ser	missense_variant	Exon 4 of 4	2	NM_001172773.2	ENSP00000337555.6
ENSG00000269533	ENST00000596400.1	c.51+5083A>G		intron_variant	Intron 2 of 3	4		ENSP00000472277.1
ENSG00000268533	ENST00000597410.1	c.39+5083A>G		intron_variant	Intron 1 of 2	3		ENSP00000472152.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151668 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000825

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

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

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250360 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135724

Gnomad AFR exome AF: 0.000770

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000171 AC: 25 AN: 1461782 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 727190

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000237 AC: 36 AN: 151786 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74184

Gnomad4 AFR AF: 0.000822

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000333 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 08, 2025

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	0.069
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.20
DEOGEN2	Benign	0.0012	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.14	T;T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.10	N;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.016
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.036
MVP		0.11
MPC		0.11
ClinPred		0.025	T
GERP RS		-2.6
Varity_R		0.012
gMVP		0.024

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

Other links and lift over

dbSNP: rs201989885; hg19: chr19-57910674;