chr19-12526978-A-G

Variant names:

• chr19-12526978-A-G
• NM_144976.4:c.1130T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_144976.4(ZNF564):​c.1130T>C​(p.Leu377Pro) 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. 15/21 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)
• Consequence: ZNF564 NM_144976.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.931

Genes affected

ZNF564 (HGNC:31106): (zinc finger protein 564) Predicted to enable DNA-binding transcription factor activity 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000196826 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05666223).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF564	NM_144976.4	c.1130T>C	p.Leu377Pro	missense_variant	Exon 4 of 4	ENST00000339282.12	NP_659413.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF564	ENST00000339282.12	c.1130T>C	p.Leu377Pro	missense_variant	Exon 4 of 4	1	NM_144976.4	ENSP00000340004.6
ENSG00000196826	ENST00000428311.1	c.3+24352T>C		intron_variant	Intron 1 of 3	2		ENSP00000404127.1
ENSG00000269693	ENST00000593682.1	n.*4108T>C		non_coding_transcript_exon_variant	Exon 4 of 4	1		ENSP00000473043.1
ENSG00000269693	ENST00000593682.1	n.*4108T>C		3_prime_UTR_variant	Exon 4 of 4	1		ENSP00000473043.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1130T>C (p.L377P) alteration is located in exon 4 (coding exon 4) of the ZNF564 gene. This alteration results from a T to C substitution at nucleotide position 1130, causing the leucine (L) at amino acid position 377 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	0.22
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.36	N
PhyloP100		-0.93
PROVEAN	Benign	0.16	N
REVEL	Benign	0.032
Sift	Benign	0.31	T
Sift4G	Benign	0.26	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.41		Gain of disorder (P = 0.0037);
MVP		0.10
MPC		0.26
ClinPred		0.053	T
GERP RS		-3.9
Varity_R		0.11
gMVP		0.16
Mutation Taster		=100/0	polymorphism

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

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Other links and lift over

hg19: chr19-12637792;