5-177044497-A-G

Position:

• chr5-177044497-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012279.4(ZNF346):​c.481A>G​(p.Asn161Asp) variant causes a missense change involving the alteration of a 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: ZNF346 NM_012279.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.50

Genes affected

ZNF346 (HGNC:16403): (zinc finger protein 346) The protein encoded by this gene is a nucleolar, zinc finger protein that preferentially binds to double-stranded (ds) RNA or RNA/DNA hybrids, rather than DNA alone. Mutational studies indicate that the zinc finger domains are not only essential for dsRNA binding, but are also required for its nucleolar localization. The encoded protein may be involved in cell growth and survival. It plays a role in protecting neurons by inhibiting cell cycle re-entry via stimulation of p21 gene expression. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Apr 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37285268).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF346	NM_012279.4	c.481A>G	p.Asn161Asp	missense_variant	4/7	ENST00000358149.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF346	ENST00000358149.8	c.481A>G	p.Asn161Asp	missense_variant	4/7	1	NM_012279.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 13, 2024

The c.481A>G (p.N161D) alteration is located in exon 4 (coding exon 4) of the ZNF346 gene. This alteration results from a A to G substitution at nucleotide position 481, causing the asparagine (N) at amino acid position 161 to be replaced by an aspartic acid (D). 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	0.92
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.;T;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Pathogenic	3.2	M;.;.;.
MutationTaster	Benign	0.64	D;D;D;D;N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.010	D;D;D;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.37	B;.;.;B
Vest4		0.41
MutPred		0.35		Loss of MoRF binding (P = 0.0357);.;Loss of MoRF binding (P = 0.0357);.;
MVP		0.70
MPC		1.0
ClinPred		0.97	D
GERP RS		4.9
Varity_R		0.39
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr5-176471498;