chr19-36877347-C-G

Position:

• chr19-36877347-C-G

Variant summary

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

The NM_001242472.2(ZNF345):​c.517C>G​(p.Pro173Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF345 NM_001242472.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF345	NM_001242472.2	c.517C>G	p.Pro173Ala	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.517C>G	p.Pro173Ala	missense_variant	3/3	1	NM_001242472.2	ENSP00000431216	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Aug 13, 2021

The c.517C>G (p.P173A) alteration is located in exon 3 (coding exon 1) of the ZNF345 gene. This alteration results from a C to G substitution at nucleotide position 517, causing the proline (P) at amino acid position 173 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	Pathogenic	0.57
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T;T;T;T;T;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.24	.;.;.;.;T;T
M_CAP	Benign	0.0036	T
MetaRNN	Uncertain	0.73	D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.9	L;L;L;L;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Pathogenic	-6.5	.;.;D;D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.010	.;.;D;D;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;.
Vest4		0.24
MutPred		0.52		Loss of ubiquitination at K177 (P = 0.0437);Loss of ubiquitination at K177 (P = 0.0437);Loss of ubiquitination at K177 (P = 0.0437);Loss of ubiquitination at K177 (P = 0.0437);Loss of ubiquitination at K177 (P = 0.0437);Loss of ubiquitination at K177 (P = 0.0437);
MVP		0.72
MPC		0.56
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.20
gMVP		0.0080

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: rs377001224; hg19: chr19-37368249;