chr19-9295846-C-G

Variant names:

• chr19-9295846-C-G
• rs766542743
• NM_198535.3:c.1558G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_198535.3(ZNF699):​c.1558G>C​(p.Val520Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF699 NM_198535.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.94
• Publications: 0 publications found

Genes affected

ZNF699 (HGNC:24750): (zinc finger protein 699) Predicted to enable DNA-binding transcription factor 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]

ZNF699 Gene-Disease associations (from GenCC):

• DEGCAGS syndrome

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09386355).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF699	NM_198535.3	c.1558G>C	p.Val520Leu	missense_variant	Exon 6 of 6	ENST00000591998.6	NP_940937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF699	ENST00000591998.6	c.1558G>C	p.Val520Leu	missense_variant	Exon 6 of 6	5	NM_198535.3	ENSP00000467723.1
ZNF699	ENST00000308650.4	c.1558G>C	p.Val520Leu	missense_variant	Exon 5 of 5	1		ENSP00000311596.3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151496 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250624 AF XY: 0.00000737

Gnomad AFR exome AF: 0.0000631

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151496 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73968

African (AFR) AF: 0.0000485 AC: 2 AN: 41228

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 306

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67860

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1558G>C (p.V520L) alteration is located in exon 5 (coding exon 5) of the ZNF699 gene. This alteration results from a G to C substitution at nucleotide position 1558, causing the valine (V) at amino acid position 520 to be replaced by a leucine (L). 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	Uncertain	0.52
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.032	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.28	.;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.72	N;N
PhyloP100		-1.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.83	.;N
REVEL	Benign	0.042
Sift	Benign	0.32	.;T
Sift4G	Benign	0.45	T;T
Polyphen		0.032	B;B
Vest4		0.13
MutPred		0.62		Gain of disorder (P = 0.0932);Gain of disorder (P = 0.0932);
MVP		0.25
MPC		0.15
ClinPred		0.042	T
GERP RS		1.1
Varity_R		0.11
gMVP		0.050
Mutation Taster		=99/1	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: rs766542743; hg19: chr19-9406522;