22-20405454-C-G

Position:

• chr22-20405454-C-G

Variant summary

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

The NM_003426.4(ZNF74):​c.421C>G​(p.Arg141Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ZNF74 NM_003426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.58

Genes affected

ZNF74 (HGNC:13144): (zinc finger protein 74) 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 actin cytoskeleton and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ZNF74 (HGNC:):

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=0.06900233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF74	NM_003426.4	c.421C>G	p.Arg141Gly	missense_variant	5/5	ENST00000400451.7	NP_003417.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF74	ENST00000400451.7	c.421C>G	p.Arg141Gly	missense_variant	5/5	1	NM_003426.4	ENSP00000383301.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460544 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

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

Jan 31, 2024

The c.421C>G (p.R141G) alteration is located in exon 5 (coding exon 5) of the ZNF74 gene. This alteration results from a C to G substitution at nucleotide position 421, causing the arginine (R) at amino acid position 141 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	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.14
DANN	Benign	0.53
DEOGEN2	Benign	0.074	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.37	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.069	T;T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.95	N;N
REVEL	Benign	0.011
Sift	Pathogenic	0.0	D;D
Vest4		0.13
MutPred		0.17		.;Gain of relative solvent accessibility (P = 0.0023);
MVP		0.030
ClinPred		0.077	T
GERP RS		-5.2

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: chr22-20759744;