chr19-36183140-C-T

Variant names:

• chr19-36183140-C-T
• rs775971742
• NM_152477.5:c.826G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_152477.5(ZNF565):​c.826G>A​(p.Glu276Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: ZNF565 NM_152477.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

Genes affected

ZNF565 (HGNC:26726): (zinc finger protein 565) 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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF565	NM_152477.5	c.826G>A	p.Glu276Lys	missense_variant	Exon 5 of 5	ENST00000304116.10	NP_689690.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF565	ENST00000304116.10	c.826G>A	p.Glu276Lys	missense_variant	Exon 5 of 5	2	NM_152477.5	ENSP00000306869.5
ZNF565	ENST00000591473.1	c.631G>A	p.Glu211Lys	missense_variant	Exon 4 of 4	1		ENSP00000465906.1
ZNF565	ENST00000355114.9	c.946G>A	p.Glu316Lys	missense_variant	Exon 5 of 5	2		ENSP00000347234.5
ZNF565	ENST00000392173.6	c.826G>A	p.Glu276Lys	missense_variant	Exon 5 of 5	2		ENSP00000376013.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251462 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135904

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

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: 0.0000103 AC: 15 AN: 1461876 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000378

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826G>A (p.E276K) alteration is located in exon 5 (coding exon 4) of the ZNF565 gene. This alteration results from a G to A substitution at nucleotide position 826, causing the glutamic acid (E) at amino acid position 276 to be replaced by a lysine (K). 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	0.60
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	.;.;T;.
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.51	T;.;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.46	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;L;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.2	D;D;D;.
REVEL	Benign	0.14
Sift	Benign	0.073	T;T;T;.
Sift4G	Uncertain	0.040	D;D;T;.
Vest4		0.37
MutPred		0.47		Gain of methylation at E276 (P = 0.0053);Gain of methylation at E276 (P = 0.0053);.;.;
MVP		0.57
MPC		1.3
ClinPred		0.93	D
GERP RS		4.4
Varity_R		0.30
gMVP		0.038

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: rs775971742; hg19: chr19-36674042; COSMIC: COSV58410966;