19-43913432-G-C

Variant names:

• chr19-43913432-G-C
• NM_003425.4:c.2004C>G

Variant summary

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

The NM_003425.4(ZNF45):​c.2004C>G​(p.Asp668Glu) 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: ZNF45 NM_003425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.35

Genes affected

ZNF45 (HGNC:13111): (zinc finger protein 45) 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. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF45-AS1 (HGNC:55308): (ZNF45 antisense RNA 1)

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=0.03831604).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF45	NM_003425.4	c.2004C>G	p.Asp668Glu	missense_variant	Exon 10 of 10	ENST00000269973.10	NP_003416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF45	ENST00000269973.10	c.2004C>G	p.Asp668Glu	missense_variant	Exon 10 of 10	2	NM_003425.4	ENSP00000269973.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 60

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2004C>G (p.D668E) alteration is located in exon 10 (coding exon 4) of the ZNF45 gene. This alteration results from a C to G substitution at nucleotide position 2004, causing the aspartic acid (D) at amino acid position 668 to be replaced by a glutamic acid (E). 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	0.084
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.28
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0046	N
LIST_S2	Benign	0.056	.;T;.
M_CAP	Benign	0.0011	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.19	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.53	N;.;.
REVEL	Benign	0.016
Sift	Benign	0.22	T;.;.
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.094
MutPred		0.26		Gain of glycosylation at K669 (P = 0.1682);Gain of glycosylation at K669 (P = 0.1682);Gain of glycosylation at K669 (P = 0.1682);
MVP		0.11
MPC		0.17
ClinPred		0.087	T
GERP RS		-5.4
Varity_R		0.029
gMVP		0.017

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-44417584;