chr19-34759486-T-C

Position:

• chr19-34759486-T-C

Variant summary

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

The NM_001007248.3(ZNF599):​c.1315A>G​(p.Ile439Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF599 NM_001007248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.846

Genes affected

ZNF599 (HGNC:26408): (zinc finger protein 599) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in negative 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08403507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF599	NM_001007248.3	c.1315A>G	p.Ile439Val	missense_variant	4/4	ENST00000329285.13	NP_001007249.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF599	ENST00000329285.13	c.1315A>G	p.Ile439Val	missense_variant	4/4	2	NM_001007248.3	ENSP00000333802.6
ZNF599	ENST00000673678.1	n.*1315A>G		non_coding_transcript_exon_variant	5/5			ENSP00000501024.1
ZNF599	ENST00000673678.1	n.*1315A>G		3_prime_UTR_variant	5/5			ENSP00000501024.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727224

Gnomad4 AFR exome AF: 0.0000597

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 18, 2022

The c.1315A>G (p.I439V) alteration is located in exon 4 (coding exon 4) of the ZNF599 gene. This alteration results from a A to G substitution at nucleotide position 1315, causing the isoleucine (I) at amino acid position 439 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.00078	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.59	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.030
Sift	Benign	0.26	T
Sift4G	Benign	0.29	T
Polyphen		0.62	P
Vest4		0.057
MutPred		0.37		Gain of relative solvent accessibility (P = 0.0522);
MVP		0.41
MPC		0.035
ClinPred		0.13	T
GERP RS		1.5
Varity_R		0.030
gMVP		0.018

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: rs2069094554; hg19: chr19-35250391;