19-55602447-C-T

Position:

• chr19-55602447-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_153219.4(ZNF524):​c.335C>T​(p.Ala112Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,443,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ZNF524 NM_153219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

Genes affected

ZNF524 (HGNC:28322): (zinc finger protein 524) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1295754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF524	NM_153219.4	c.335C>T	p.Ala112Val	missense_variant	2/2	ENST00000301073.4	NP_694951.1
ZNF524	XM_011526487.3	c.653C>T	p.Ala218Val	missense_variant	2/2		XP_011524789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF524	ENST00000301073.4	c.335C>T	p.Ala112Val	missense_variant	2/2	1	NM_153219.4	ENSP00000301073.2
ZNF524	ENST00000591046.1	c.335C>T	p.Ala112Val	missense_variant	1/1	6		ENSP00000466907.1
ZNF524	ENST00000589521.1	c.335C>T	p.Ala112Val	missense_variant	2/2	3		ENSP00000467175.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1443304 Hom.: 0 Cov.: 29 AF XY: 0.00000418 AC XY: 3 AN XY: 717378

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: 0.00000723

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

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

Jul 15, 2021

The c.335C>T (p.A112V) alteration is located in exon 2 (coding exon 1) of the ZNF524 gene. This alteration results from a C to T substitution at nucleotide position 335, causing the alanine (A) at amino acid position 112 to be replaced by a valine (V). 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.56	T;.;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.13	.;N;.
REVEL	Benign	0.074
Sift	Benign	0.11	.;T;.
Sift4G	Benign	0.065	T;T;T
Polyphen		0.96	.;D;D
Vest4		0.11, 0.099
MutPred		0.40		Loss of ubiquitination at K111 (P = 0.0421);Loss of ubiquitination at K111 (P = 0.0421);Loss of ubiquitination at K111 (P = 0.0421);
MVP		0.26
MPC		0.50
ClinPred		0.36	T
GERP RS		3.3
Varity_R		0.050
gMVP		0.38

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: rs769617389; hg19: chr19-56113813;