16-3408376-A-C

Position:

• chr16-3408376-A-C

Variant summary

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

The NM_003450.3(ZNF174):​c.681A>C​(p.Lys227Asn) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF174 NM_003450.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.222

Genes affected

ZNF174 (HGNC:12963): (zinc finger protein 174) This gene encodes a protein with three Cys2-His2-type zinc fingers in the carboxy-terminus, a putative nuclear localization signal, and an amino-terminus SCAN box which forms homodimers. This protein is believed to function as a transcriptional repressor. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Dec 2016]

ENSG00000285329 (HGNC:):

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=0.06697571).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF174	NM_003450.3	c.681A>C	p.Lys227Asn	missense_variant	3/3	ENST00000268655.5	NP_003441.1
ZNF174	NM_001347868.2	c.681A>C	p.Lys227Asn	missense_variant	4/4		NP_001334797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF174	ENST00000268655.5	c.681A>C	p.Lys227Asn	missense_variant	3/3	1	NM_003450.3	ENSP00000268655.4
ENSG00000285329	ENST00000575785.2	n.211+3728A>C		intron_variant		4		ENSP00000477472.1
ZNF174	ENST00000571936.5	c.681A>C	p.Lys227Asn	missense_variant	4/4	5		ENSP00000460397.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250788 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135556

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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 15, 2023

The c.681A>C (p.K227N) alteration is located in exon 3 (coding exon 3) of the ZNF174 gene. This alteration results from a A to C substitution at nucleotide position 681, causing the lysine (K) at amino acid position 227 to be replaced by an asparagine (N). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.051	T;T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.0020	N
LIST_S2	Benign	0.54	.;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L;L
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.5	.;N
REVEL	Benign	0.031
Sift	Benign	0.33	.;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0010	B;B
Vest4		0.054
MutPred		0.42		Loss of ubiquitination at K227 (P = 0.0011);Loss of ubiquitination at K227 (P = 0.0011);
MVP		0.24
MPC		0.49
ClinPred		0.032	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.28

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: rs747448141; hg19: chr16-3458376;