1-248850506-A-T

Variant names:

• chr1-248850506-A-T
• rs1284018263
• NM_017865.4:c.1264T>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_017865.4(ZNF692):​c.1264T>A​(p.Cys422Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. C422R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF692 NM_017865.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

Genes affected

ZNF692 (HGNC:26049): (zinc finger protein 692) Enables DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in negative regulation of transcription by RNA polymerase II and regulation of gluconeogenesis. Located in nucleolus and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF692	NM_017865.4	c.1264T>A	p.Cys422Ser	missense_variant	Exon 12 of 12	ENST00000306601.9	NP_060335.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF692	ENST00000306601.9	c.1264T>A	p.Cys422Ser	missense_variant	Exon 12 of 12	1	NM_017865.4	ENSP00000305483.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455006 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 723056

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: 0.00000541

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1279T>A (p.C427S) alteration is located in exon 12 (coding exon 12) of the ZNF692 gene. This alteration results from a T to A substitution at nucleotide position 1279, causing the cysteine (C) at amino acid position 427 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	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	3.6	H;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.6	D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;P;.
Vest4		0.94
MutPred		0.94		Gain of glycosylation at C422 (P = 0.0349);.;.;
MVP		0.78
MPC		0.83
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.63

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: rs1284018263; hg19: chr1-249144705;