19-34759170-A-G

Position:

• chr19-34759170-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001007248.3(ZNF599):​c.1631T>C​(p.Phe544Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF599 NM_001007248.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.61

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF599	NM_001007248.3	c.1631T>C	p.Phe544Ser	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.1631T>C	p.Phe544Ser	missense_variant	4/4	2	NM_001007248.3	ENSP00000333802.6
ZNF599	ENST00000673678.1	n.*1631T>C		non_coding_transcript_exon_variant	5/5			ENSP00000501024.1
ZNF599	ENST00000673678.1	n.*1631T>C		3_prime_UTR_variant	5/5			ENSP00000501024.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Sep 12, 2023

The c.1631T>C (p.F544S) alteration is located in exon 4 (coding exon 4) of the ZNF599 gene. This alteration results from a T to C substitution at nucleotide position 1631, causing the phenylalanine (F) at amino acid position 544 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	0.97
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.86	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.44
Sift	Benign	0.078	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.73		Gain of ubiquitination at K542 (P = 0.0505);
MVP		0.70
MPC		0.31
ClinPred		0.98	D
GERP RS		1.4
Varity_R		0.47
gMVP		0.25

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: rs1568491529; hg19: chr19-35250075;