20-49247506-C-T

Variant names:

• chr20-49247506-C-T
• NM_021035.3:c.5518G>A

Variant summary

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

The NM_021035.3(ZNFX1):​c.5518G>A​(p.Gly1840Ser) 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 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNFX1 NM_021035.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.64

Genes affected

ZNFX1 (HGNC:29271): (zinc finger NFX1-type containing 1) Enables RNA binding activity. Predicted to be involved in heterochromatin assembly by small RNA. Predicted to be part of nuclear RNA-directed RNA polymerase complex. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
ZNFX1	NM_021035.3	c.5518G>A	p.Gly1840Ser	missense_variant	Exon 14 of 14	ENST00000396105.6	NP_066363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNFX1	ENST00000396105.6	c.5518G>A	p.Gly1840Ser	missense_variant	Exon 14 of 14	1	NM_021035.3	ENSP00000379412.1
ZNFX1	ENST00000371754.8	c.3312+4021G>A		intron_variant	Intron 13 of 14	1		ENSP00000360819.4
ZNFX1	ENST00000371752.5	c.5518G>A	p.Gly1840Ser	missense_variant	Exon 14 of 14	5		ENSP00000360817.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5518G>A (p.G1840S) alteration is located in exon 14 (coding exon 13) of the ZNFX1 gene. This alteration results from a G to A substitution at nucleotide position 5518, causing the glycine (G) at amino acid position 1840 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	.;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.023	D;D
Polyphen		1.0	D;D
Vest4		0.49
MutPred		0.49		Gain of sheet (P = 0.0149);Gain of sheet (P = 0.0149);
MVP		0.56
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.34
gMVP		0.52

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: chr20-47864043;