chr19-36183553-A-G

Position:

• chr19-36183553-A-G

Variant summary

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

The NM_152477.5(ZNF565):​c.413T>C​(p.Val138Ala) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: ZNF565 NM_152477.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0150

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048612654).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF565	NM_152477.5	c.413T>C	p.Val138Ala	missense_variant	5/5	ENST00000304116.10	NP_689690.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF565	ENST00000304116.10	c.413T>C	p.Val138Ala	missense_variant	5/5	2	NM_152477.5	ENSP00000306869.5
ZNF565	ENST00000591473.1	c.218T>C	p.Val73Ala	missense_variant	4/4	1		ENSP00000465906.1
ZNF565	ENST00000355114.9	c.533T>C	p.Val178Ala	missense_variant	5/5	2		ENSP00000347234.5
ZNF565	ENST00000392173.6	c.413T>C	p.Val138Ala	missense_variant	5/5	2		ENSP00000376013.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

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

May 11, 2022

The c.413T>C (p.V138A) alteration is located in exon 5 (coding exon 4) of the ZNF565 gene. This alteration results from a T to C substitution at nucleotide position 413, causing the valine (V) at amino acid position 138 to be replaced by an alanine (A). 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	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.8
DANN	Benign	0.44
DEOGEN2	Benign	0.018	.;.;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.083	N
LIST_S2	Benign	0.054	T;.;T;T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.049	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M;M;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.44	N;N;N;.
REVEL	Benign	0.053
Sift	Benign	0.48	T;T;T;.
Sift4G	Benign	0.56	T;T;T;.
Vest4		0.26
MutPred		0.26		Loss of stability (P = 0.1672);Loss of stability (P = 0.1672);.;.;
MVP		0.19
MPC		0.48
ClinPred		0.14	T
GERP RS		3.6
Varity_R		0.034
gMVP		0.053

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: rs1975168421; hg19: chr19-36674455;