20-33732051-G-A

Variant names:

• chr20-33732051-G-A
• rs201085406
• NM_001282933.2:c.30G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001282933.2(ZNF341):​c.30G>A​(p.Glu10Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000108 in 1,300,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000061 (0 hom.)
• Consequence: ZNF341 NM_001282933.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.002945
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 0 publications found

Genes affected

ZNF341 (HGNC:15992): (zinc finger protein 341) Enables DNA binding activity and DNA-binding transcription activator activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in nucleus. Implicated in hyper IgE recurrent infection syndrome 3. [provided by Alliance of Genome Resources, Apr 2022]

ZNF341 Gene-Disease associations (from GenCC):

• hyper-IgE recurrent infection syndrome 3, autosomal recessive

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

ENSG00000229188 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF341	NM_001282933.2	c.30G>A	p.Glu10Glu	splice_region_variant, synonymous_variant	Exon 1 of 15	ENST00000375200.6	NP_001269862.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF341	ENST00000375200.6	c.30G>A	p.Glu10Glu	splice_region_variant, synonymous_variant	Exon 1 of 15	1	NM_001282933.2	ENSP00000364346.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151714 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000610 AC: 7 AN: 1148270 Hom.: 0 Cov.: 30 AF XY: 0.0000127 AC XY: 7 AN XY: 553262

African (AFR) AF: 0.00 AC: 0 AN: 23166

American (AMR) AF: 0.00 AC: 0 AN: 9390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15954

East Asian (EAS) AF: 0.0000372 AC: 1 AN: 26854

South Asian (SAS) AF: 0.00 AC: 0 AN: 39494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3618

European-Non Finnish (NFE) AF: 0.00000631 AC: 6 AN: 950528

Other (OTH) AF: 0.00 AC: 0 AN: 45734

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151822 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74242

African (AFR) AF: 0.00 AC: 0 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000884 AC: 6 AN: 67866

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with ZNF341-related conditions. This variant is present in population databases (rs201085406, gnomAD 0.007%). This sequence change affects codon 10 of the ZNF341 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ZNF341 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.98
PhyloP100		1.2
PromoterAI		0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0029
dbscSNV1_RF	Benign	0.094
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: rs201085406; hg19: chr20-32319857;