19-36877024-A-C

Position:

• chr19-36877024-A-C

Variant summary

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

The NM_001242472.2(ZNF345):​c.194A>C​(p.Lys65Thr) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF345 NM_001242472.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.23

Genes affected

ZNF345 (HGNC:16367): (zinc finger protein 345) Enables sequence-specific double-stranded 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]

ENSG00000291239 (HGNC:):

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=0.14042163).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF345	NM_001242472.2	c.194A>C	p.Lys65Thr	missense_variant	3/3	ENST00000420450.6	NP_001229401.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF345	ENST00000420450.6	c.194A>C	p.Lys65Thr	missense_variant	3/3	1	NM_001242472.2	ENSP00000431216.1
ENSG00000291239	ENST00000706165.1	c.-423-15794A>C		intron_variant				ENSP00000516244.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Dec 04, 2024

The c.194A>C (p.K65T) alteration is located in exon 3 (coding exon 1) of the ZNF345 gene. This alteration results from a A to C substitution at nucleotide position 194, causing the lysine (K) at amino acid position 65 to be replaced by a threonine (T). 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	0.13
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;T;.;T;T;.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.22	.;.;T;.;.;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N;.;N;N;.;N;.;.
PrimateAI	Benign	0.26	T
PROVEAN	Pathogenic	-5.3	.;.;D;D;D;D;.;.;.
REVEL	Benign	0.095
Sift	Uncertain	0.0030	.;.;D;T;T;D;.;.;.
Sift4G	Uncertain	0.031	D;D;D;D;D;D;D;T;D
Polyphen		0.26	B;B;.;B;B;.;B;.;.
Vest4		0.16
MutPred		0.31		Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);Loss of methylation at K65 (P = 3e-04);
MVP		0.58
MPC		0.51
ClinPred		0.50	T
GERP RS		4.4
Varity_R		0.16
gMVP		0.025

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: rs199538028; hg19: chr19-37367926;