rs3746554

Variant names:

• chr20-49270339-T-C
• rs3746554
• NM_021035.3:c.1473A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_021035.3(ZNFX1):​c.1473A>G​(p.Gln491Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 1,614,170 control chromosomes in the GnomAD database, including 722 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.021 (661 hom.)
• Consequence: ZNFX1 NM_021035.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0110
• Publications: 8 publications found

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]

ZNFX1 Gene-Disease associations (from GenCC):

• immunodeficiency 91 and hyperinflammation

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP7: Synonymous conserved (PhyloP=0.011 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0648 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNFX1	NM_021035.3	MANE Select	c.1473A>G	p.Gln491Gln	synonymous	Exon 3 of 14	NP_066363.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNFX1	ENST00000396105.6	TSL:1 MANE Select	c.1473A>G	p.Gln491Gln	synonymous	Exon 3 of 14	ENSP00000379412.1
	ZNFX1	ENST00000371754.8	TSL:1	c.1473A>G	p.Gln491Gln	synonymous	Exon 3 of 15	ENSP00000360819.4
	ZNFX1	ENST00000371752.5	TSL:5	c.1473A>G	p.Gln491Gln	synonymous	Exon 3 of 14	ENSP00000360817.1

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2323 AN: 152236 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00285

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0224

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0611

Gnomad SAS AF: 0.0715

Gnomad FIN AF: 0.00838

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0167

GnomAD2 exomes AF: 0.0249 AC: 6229 AN: 250624 AF XY: 0.0257

Gnomad AFR exome AF: 0.00327

Gnomad AMR exome AF: 0.0354

Gnomad ASJ exome AF: 0.00627

Gnomad EAS exome AF: 0.0496

Gnomad FIN exome AF: 0.00971

Gnomad NFE exome AF: 0.0144

Gnomad OTH exome AF: 0.0213

GnomAD4 exome AF: 0.0207 AC: 30262 AN: 1461816 Hom.: 661 Cov.: 35 AF XY: 0.0217 AC XY: 15778 AN XY: 727204

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.0345 AC: 1542 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00639 AC: 167 AN: 26136

East Asian (EAS) AF: 0.0913 AC: 3626 AN: 39698

South Asian (SAS) AF: 0.0632 AC: 5453 AN: 86258

European-Finnish (FIN) AF: 0.0100 AC: 536 AN: 53374

Middle Eastern (MID) AF: 0.00763 AC: 44 AN: 5768

European-Non Finnish (NFE) AF: 0.0157 AC: 17511 AN: 1111984

Other (OTH) AF: 0.0213 AC: 1285 AN: 60394

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152354 Hom.: 61 Cov.: 32 AF XY: 0.0163 AC XY: 1212 AN XY: 74514

African (AFR) AF: 0.00284 AC: 118 AN: 41590

American (AMR) AF: 0.0226 AC: 346 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.0612 AC: 318 AN: 5192

South Asian (SAS) AF: 0.0710 AC: 343 AN: 4834

European-Finnish (FIN) AF: 0.00838 AC: 89 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0149 AC: 1013 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0150 Hom.: 47

Bravo AF: 0.0142

Asia WGS AF: 0.0890 AC: 309 AN: 3478

EpiCase AF: 0.0138

EpiControl AF: 0.0139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	4.6
DANN	Benign	0.66
PhyloP100		0.011
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3746554; hg19: chr20-47886876; COSMIC: COSV65579104;