19-57538236-A-G

Position:

• chr19-57538236-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001199295.2(ZNF549):​c.1232A>G​(p.His411Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF549 NM_001199295.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.98

Genes affected

ZNF549 (HGNC:26632): (zinc finger protein 549) 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]

ZNF550 (HGNC:28643): (zinc finger protein 550) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF549	NM_001199295.2	c.1232A>G	p.His411Arg	missense_variant	4/4	ENST00000376233.8	NP_001186224.2
ZNF549	NM_153263.3	c.1193A>G	p.His398Arg	missense_variant	3/3		NP_694995.3
ZNF549	XM_047438563.1	c.1319A>G	p.His440Arg	missense_variant	3/3		XP_047294519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF549	ENST00000376233.8	c.1232A>G	p.His411Arg	missense_variant	4/4	1	NM_001199295.2	ENSP00000365407	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1232A>G (p.H411R) alteration is located in exon 4 (coding exon 4) of the ZNF549 gene. This alteration results from a A to G substitution at nucleotide position 1232, causing the histidine (H) at amino acid position 411 to be replaced by an arginine (R). 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	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0080	T
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.0	.;M
MutationTaster	Benign	0.92	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.0	D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.41
MutPred		0.83		.;Gain of MoRF binding (P = 0.0854);
MVP		0.68
MPC		0.41
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.80
gMVP		0.26

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: chr19-58049604;