5-124644459-G-C

Position:

• chr5-124644459-G-C

Variant summary

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

The NM_020747.3(ZNF608):​c.3908C>G​(p.Ser1303Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000197 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 32)
• Consequence: ZNF608 NM_020747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.97

Genes affected

ZNF608 (HGNC:29238): (zinc finger protein 608) Predicted to enable metal ion binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF608 (HGNC:):

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=0.18991059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF608	NM_020747.3	c.3908C>G	p.Ser1303Cys	missense_variant	6/10	ENST00000513986.2	NP_065798.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF608	ENST00000513986.2	c.3908C>G	p.Ser1303Cys	missense_variant	6/10	2	NM_020747.3	ENSP00000421899.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152096 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74276

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

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

Aug 11, 2024

The c.3908C>G (p.S1303C) alteration is located in exon 5 (coding exon 5) of the ZNF608 gene. This alteration results from a C to G substitution at nucleotide position 3908, causing the serine (S) at amino acid position 1303 to be replaced by a cysteine (C). 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	0.075
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	.;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.17
Sift	Benign	0.66	T;T
Sift4G	Benign	0.16	T;T
Polyphen		1.0	.;D
Vest4		0.37
MutPred		0.13		.;Loss of phosphorylation at S1303 (P = 0.0057);
MVP		0.043
MPC		0.63
ClinPred		0.71	D
GERP RS		5.5
Varity_R		0.17
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: rs1294340633; hg19: chr5-123980152;