19-58185754-G-A

Position:

• chr19-58185754-G-A

Variant summary

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

The NM_133502.3(ZNF274):​c.76G>A​(p.Glu26Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000761 in 1,313,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: ZNF274 NM_133502.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

Genes affected

ZNF274 (HGNC:13068): (zinc finger protein 274) This gene encodes a zinc finger protein containing five C2H2-type zinc finger domains, one or two Kruppel-associated box A (KRAB A) domains, and a leucine-rich domain. The encoded protein has been suggested to be a transcriptional repressor. It localizes predominantly to the nucleolus. Alternatively spliced transcript variants encoding different isoforms exist. These variants utilize alternative polyadenylation signals. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF274	NM_133502.3	c.76G>A	p.Glu26Lys	missense_variant	3/8	ENST00000617501.5	NP_598009.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF274	ENST00000617501.5	c.76G>A	p.Glu26Lys	missense_variant	3/8	1	NM_133502.3	ENSP00000484810	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.61e-7 AC: 1 AN: 1313342 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 649610

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: 9.66e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

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 12, 2024

The c.76G>A (p.E26K) alteration is located in exon 3 (coding exon 2) of the ZNF274 gene. This alteration results from a G to A substitution at nucleotide position 76, causing the glutamic acid (E) at amino acid position 26 to be replaced by a lysine (K). 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	0.20
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.092	.;T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;.;T;T
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	0.68	D;D;D
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.091	T;.;.;.
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.93	P;P;P;.
Vest4		0.38
MutPred		0.74		Gain of methylation at E26 (P = 0.0126);Gain of methylation at E26 (P = 0.0126);Gain of methylation at E26 (P = 0.0126);Gain of methylation at E26 (P = 0.0126);
MVP		0.54
ClinPred		0.80	D
GERP RS		4.2
Varity_R		0.10
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1433564705; hg19: chr19-58697121; COSMIC: COSV58766086; COSMIC: COSV58766086;