rs193921040

Positions:

• chr3-75738395-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001290208.3(ZNF717):​c.1228C>G​(p.Leu410Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 1,538,504 control chromosomes in the GnomAD database, including 326 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.034 (40 hom., cov: 48)
  • Exomes 𝑓: 0.030 (286 hom.)
• Consequence: ZNF717 NM_001290208.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.13

Genes affected

ZNF717 (HGNC:29448): (zinc finger protein 717) This gene encodes a Kruppel-associated box (KRAB) zinc-finger protein, which belongs to a large group of transcriptional regulators in mammals. These proteins bind nucleic acids and play important roles in various cellular functions, including cell proliferation, differentiation and apoptosis, and in regulating viral replication and transcription. A pseudogene of this gene was identified on chromosome 1. [provided by RefSeq, May 2016]

LINC00960 (HGNC:48710): (long intergenic non-protein coding RNA 960)

MIR4273 (HGNC:38339): (microRNA 4273) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046102107).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0556 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF717	NM_001290208.3	c.1228C>G	p.Leu410Val	missense_variant	5/5	ENST00000652011.2	NP_001277137.1
MIR4273	NR_036235.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF717	ENST00000652011.2	c.1228C>G	p.Leu410Val	missense_variant	5/5		NM_001290208.3	ENSP00000498738	P1
LINC00960	ENST00000668145.1	n.471-2198G>C		intron_variant, non_coding_transcript_variant
MIR4273	ENST00000582824.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5175 AN: 151752 Hom.: 41 Cov.: 48

Gnomad AFR AF: 0.0576

Gnomad AMI AF: 0.0232

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0592

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0268

Gnomad OTH AF: 0.0264

GnomAD3 exomes AF: 0.0000358 AC: 1 AN: 27922 Hom.: 0 AF XY: 0.0000702 AC XY: 1 AN XY: 14238

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000296

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0304 AC: 42103 AN: 1386634 Hom.: 286 Cov.: 75 AF XY: 0.0313 AC XY: 21395 AN XY: 683928

Gnomad4 AFR exome AF: 0.0585

Gnomad4 AMR exome AF: 0.0189

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.000171

Gnomad4 SAS exome AF: 0.0677

Gnomad4 FIN exome AF: 0.0182

Gnomad4 NFE exome AF: 0.0287

Gnomad4 OTH exome AF: 0.0315

GnomAD4 genome AF: 0.0341 AC: 5174 AN: 151870 Hom.: 40 Cov.: 48 AF XY: 0.0335 AC XY: 2484 AN XY: 74252

Gnomad4 AFR AF: 0.0575

Gnomad4 AMR AF: 0.0246

Gnomad4 ASJ AF: 0.0228

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0588

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0268

Gnomad4 OTH AF: 0.0261

Alfa AF: 0.0360 Hom.: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Malignant tumor of prostate Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Uncertain	1.0
Eigen	Benign	0.088
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Vest4		0.11
MVP		0.12
ClinPred		0.38	T
GERP RS		1.7
gMVP		0.0014

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: rs193921040; hg19: chr3-75787546; COSMIC: COSV68867527; COSMIC: COSV68867527;