10-38054416-A-G

Position:

• chr10-38054416-A-G

Variant summary

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

The NM_006954.2(ZNF33A):​c.292A>G​(p.Asn98Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,440,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000014 (0 hom.)
• Consequence: ZNF33A NM_006954.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

Genes affected

ZNF33A (HGNC:13096): (zinc finger protein 33A) Predicted to enable DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.07504812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF33A	NM_006954.2	c.292A>G	p.Asn98Asp	missense_variant	5/5	ENST00000432900.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF33A	ENST00000432900.7	c.292A>G	p.Asn98Asp	missense_variant	5/5	1	NM_006954.2	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1440982 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 715614

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000480 Hom.: 0

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 10, 2023

The c.292A>G (p.N98D) alteration is located in exon 5 (coding exon 4) of the ZNF33A gene. This alteration results from a A to G substitution at nucleotide position 292, causing the asparagine (N) at amino acid position 98 to be replaced by an aspartic acid (D). 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	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.033	T;.;.;T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.085	T;T;T;T;T
M_CAP	Benign	0.00033	T
MetaRNN	Benign	0.075	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	.;.;.;D;N
REVEL	Benign	0.023
Sift	Benign	0.058	.;.;.;T;T
Sift4G	Benign	0.50	T;T;T;T;T
Polyphen		0.058, 0.0070	.;.;.;B;B
Vest4		0.061
MutPred		0.31		.;.;.;Loss of methylation at K100 (P = 0.0831);.;
MVP		0.12
ClinPred		0.15	T
GERP RS		0.27
Varity_R		0.14
gMVP		0.034

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: rs2066352345; hg19: chr10-38343344;