6-87155652-G-A

Variant names:

• chr6-87155652-G-A
• rs1770500301
• NM_015021.3:c.61G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5 BP4 BS2

The NM_015021.3(ZNF292):​c.61G>A​(p.Glu21Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000769 in 1,430,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: ZNF292 NM_015021.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.70
• Publications: 0 publications found

Genes affected

ZNF292 (HGNC:18410): (zinc finger protein 292) This gene encodes a growth hormone-dependent, zinc finger transcription factor that functions as a tumor suppressor. Naturally occurring mutations in this gene are associated with gastric cancer, colorectal cancer, and chronic lymphocytic leukemia. [provided by RefSeq, May 2017]

ZNF292 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen
• intellectual developmental disorder, autosomal dominant 64

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ENSG00000272008 (HGNC:):

ACMG classification

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

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-87155652-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2576539.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34573093).
• BS2: High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF292	NM_015021.3	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 8	ENST00000369577.8	NP_055836.1
ZNF292	NM_001351444.2	c.-505G>A		5_prime_UTR_variant	Exon 1 of 9		NP_001338373.1
ZNF292	XM_047418459.1	c.-673G>A		5_prime_UTR_variant	Exon 1 of 10		XP_047274415.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF292	ENST00000369577.8	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 8	1	NM_015021.3	ENSP00000358590.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000769 AC: 11 AN: 1430782 Hom.: 0 Cov.: 31 AF XY: 0.00000564 AC XY: 4 AN XY: 708786

African (AFR) AF: 0.00 AC: 0 AN: 32964

American (AMR) AF: 0.00 AC: 0 AN: 39702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25510

East Asian (EAS) AF: 0.00 AC: 0 AN: 38176

South Asian (SAS) AF: 0.00 AC: 0 AN: 81886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4776

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1098406

Other (OTH) AF: 0.00 AC: 0 AN: 59194

GnomAD4 genome Cov.: 33

Alfa AF: 0.000112 Hom.: 1

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder, autosomal dominant 64 Uncertain:1

Jun 04, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at position 61 of the coding sequence of the ZNF292 gene that results in a glutamic acid to lysine amino acid change at residue 21 of zinc finger protein 292. This variant is present in 11 of 1583162 alleles (0.00078%) in the gnomAD v4.1.0 population dataset and has not been observed in individuals affected by ZNF292-related conditions in the published literature, to our knowledge. Multiple bioinformatic tools provide conflicting predictions concerning the impact of this amino acid change, and the Glu21 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant have not been published, to our knowledge. At this time, there is insufficient evidence to determine if this variant is pathogenic or benign. Therefore, we consider this a variant of uncertain significance. ACMG Criteria: PM2, PM5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.35	T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.6	.;L;.;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;N;N;N
REVEL	Benign	0.068
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;T;D;T
Polyphen		0.82	.;P;.;.
Vest4		0.46
MVP		0.082
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		0.0093	Neutral
Varity_R		0.28
gMVP		0.54
Mutation Taster		=71/29	polymorphism

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: rs1770500301; hg19: chr6-87865370;