1-42851733-A-C

Position:

• chr1-42851733-A-C

Variant summary

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

The NM_001242739.2(ZNF691):​c.868A>C​(p.Lys290Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ZNF691 NM_001242739.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26

Genes affected

ZNF691 (HGNC:28028): (zinc finger protein 691) Predicted to enable DNA-binding transcription factor activity 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 located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF691	NM_001242739.2	c.868A>C	p.Lys290Gln	missense_variant	4/4	ENST00000651192.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF691	ENST00000651192.1	c.868A>C	p.Lys290Gln	missense_variant	4/4		NM_001242739.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Nov 09, 2023

The c.868A>C (p.K290Q) alteration is located in exon 4 (coding exon 2) of the ZNF691 gene. This alteration results from a A to C substitution at nucleotide position 868, causing the lysine (K) at amino acid position 290 to be replaced by a glutamine (Q). 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	0.79
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.;T;T;T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;.;.;D;.;T;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.50	T;T;T;T;T;T;T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.6	L;.;.;.;.;.;.
MutationTaster	Benign	0.88	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.5	.;D;D;D;D;D;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	.;D;D;D;D;D;.
Sift4G	Uncertain	0.050	T;T;T;T;D;T;D
Polyphen		1.0	D;.;.;.;.;.;.
Vest4		0.65
MutPred		0.53		Loss of methylation at K290 (P = 0.0012);.;.;.;.;Loss of methylation at K290 (P = 0.0012);.;
MVP		0.29
ClinPred		0.96	D
GERP RS		4.0
Varity_R		0.51
gMVP		0.16

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: rs1655401099; hg19: chr1-43317404;