6-27451689-G-C

Variant summary

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

The NM_001318891.2(ZNF184):c.1870C>G(p.Arg624Gly) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF184 NM_001318891.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

Genes affected

ZNF184 (HGNC:12975): (zinc finger protein 184) The protein encoded by this gene is predicted to be a Kruppel C2H2-type zinc-finger protein family member. Sequence analysis predicts that the protein contains two Kruppel associated box (KRAB) boxes in the N-terminus and highly conserved zinc finger motifs at the C-terminus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2016]

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=0.11849317).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF184	NM_001318891.2	c.1870C>G	p.Arg624Gly	missense_variant	6/6	ENST00000683788.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF184	ENST00000683788.1	c.1870C>G	p.Arg624Gly	missense_variant	6/6		NM_001318891.2	P1
ZNF184	ENST00000211936.10	c.1870C>G	p.Arg624Gly	missense_variant	6/6	1		P1
ZNF184	ENST00000377419.1	c.1870C>G	p.Arg624Gly	missense_variant	6/6	4		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Apr 27, 2022

The c.1870C>G (p.R624G) alteration is located in exon 6 (coding exon 5) of the ZNF184 gene. This alteration results from a C to G substitution at nucleotide position 1870, causing the arginine (R) at amino acid position 624 to be replaced by a glycine (G). 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	0.80
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.00088	N
LIST_S2	Benign	0.047	T;.
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.17
Sift	Benign	0.047	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.030	B;B
Vest4		0.45
MutPred		0.46		Loss of catalytic residue at R624 (P = 0.0523);Loss of catalytic residue at R624 (P = 0.0523);
MVP		0.29
MPC		1.5
ClinPred		0.53	D
GERP RS		3.2
Varity_R		0.21
gMVP		0.26

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: rs774034887; hg19: chr6-27419468;