19-58246367-G-C

Variant names:

• chr19-58246367-G-C
• rs2045220900
• NM_014480.4:c.100G>C

Variant summary

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

The NM_014480.4(ZNF544):​c.100G>C​(p.Ala34Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ZNF544 NM_014480.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.210

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:):

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
ZNF544	NM_014480.4	c.100G>C	p.Ala34Pro	missense_variant	Exon 5 of 7	ENST00000687789.1	NP_055295.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF544	ENST00000687789.1	c.100G>C	p.Ala34Pro	missense_variant	Exon 5 of 7		NM_014480.4	ENSP00000510489.1
ENSG00000283515	ENST00000637233.1	n.100G>C		non_coding_transcript_exon_variant	Exon 5 of 12	5		ENSP00000490395.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 20 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

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: 0.0000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000930 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.100G>C (p.A34P) alteration is located in exon 5 (coding exon 2) of the ZNF544 gene. This alteration results from a G to C substitution at nucleotide position 100, causing the alanine (A) at amino acid position 34 to be replaced by a proline (P). 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	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.57
DEOGEN2	Benign	0.0085	.;.;.;.;T;T;T;.;.;.;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.11	.;T;.;T;.;.;T;T;T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Uncertain	0.44	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	.;.;.;.;L;.;.;.;.;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-2.5	.;.;.;.;.;.;.;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.072	.;.;.;.;.;.;.;.;.;.;T
Sift4G	Uncertain	0.0090	D;D;D;D;T;T;T;D;D;D;T
Polyphen		0.99	.;.;.;.;D;.;.;.;.;.;D
Vest4		0.44
MutPred		0.79		Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP		0.18
MPC		0.13
ClinPred		0.50	T
GERP RS		-0.20
Varity_R		0.25
gMVP		0.46

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: rs2045220900; hg19: chr19-58757733;