19-58260984-A-C

Variant names:

• chr19-58260984-A-C
• rs2048810018
• NM_014480.4:c.378A>C

Variant summary

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

The NM_014480.4(ZNF544):​c.378A>C​(p.Gln126His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 32)
• Consequence: ZNF544 NM_014480.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.91

Genes affected

ZNF544 (HGNC:16759): (zinc finger protein 544) Predicted to enable DNA-binding transcription activator 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]

ENSG00000283515 (HGNC:):

ZNF8-DT (HGNC:55280): (ZNF8 divergent transcript)

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=0.056965113).
• BP6: Variant 19-58260984-A-C is Benign according to our data. Variant chr19-58260984-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2311058.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF544	NM_014480.4	c.378A>C	p.Gln126His	missense_variant	Exon 7 of 7	ENST00000687789.1	NP_055295.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF544	ENST00000687789.1	c.378A>C	p.Gln126His	missense_variant	Exon 7 of 7		NM_014480.4	ENSP00000510489.1
ENSG00000283515	ENST00000637233.1	n.209+14190A>C		intron_variant	Intron 6 of 11	5		ENSP00000490395.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 07, 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	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.056
DANN	Benign	0.16
DEOGEN2	Benign	0.0031	T;T;T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.000030	N
LIST_S2	Benign	0.41	.;.;T;T
M_CAP	Benign	0.00051	T
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N;.;.;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.3	.;.;.;N
REVEL	Benign	0.046
Sift	Benign	0.54	.;.;.;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.0070	B;.;.;B
Vest4		0.12
MutPred		0.27		Gain of catalytic residue at D127 (P = 0.1487);.;.;Gain of catalytic residue at D127 (P = 0.1487);
MVP		0.067
MPC		0.020
ClinPred		0.026	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.029
gMVP		0.097

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: rs2048810018; hg19: chr19-58772350;