19-9413878-T-C

Variant names:

• chr19-9413878-T-C
• rs2068589644
• NM_001370374.1:c.1248A>G

Variant summary

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

The NM_001370374.1(ZNF266):​c.1248A>G​(p.Ile416Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF266 NM_001370374.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.65

Genes affected

ZNF266 (HGNC:13059): (zinc finger protein 266) This gene encodes a protein containing many tandem zinc-finger motifs. Zinc fingers are protein or nucleic acid-binding domains, and may be involved in a variety of functions, including regulation of transcription. This gene is located in a cluster of similar genes encoding zinc finger proteins on chromosome 19. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Sep 2012]

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=0.090223074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF266	NM_001370374.1	c.1248A>G	p.Ile416Met	missense_variant	Exon 11 of 11	ENST00000592904.7	NP_001357303.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF266	ENST00000592904.7	c.1248A>G	p.Ile416Met	missense_variant	Exon 11 of 11	1	NM_001370374.1	ENSP00000466714.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727246

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1047A>G (p.I349M) alteration is located in exon 11 (coding exon 4) of the ZNF266 gene. This alteration results from a A to G substitution at nucleotide position 1047, causing the isoleucine (I) at amino acid position 349 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.030	.;T;T;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.000090	N
LIST_S2	Benign	0.089	T;.;.;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.090	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	.;N;N;N;N
PrimateAI	Benign	0.27	T
Sift4G	Pathogenic	0.0	.;D;D;D;D
Polyphen		0.94	.;P;P;P;P
Vest4		0.084, 0.082, 0.085, 0.083
MutPred		0.40		.;Loss of methylation at K350 (P = 0.0332);Loss of methylation at K350 (P = 0.0332);Loss of methylation at K350 (P = 0.0332);Loss of methylation at K350 (P = 0.0332);
MVP		0.21
MPC		0.20
ClinPred		0.55	D
GERP RS		-4.5
Varity_R		0.038

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: rs2068589644; hg19: chr19-9524554;