chr3-75738395-G-A

Variant names:

• chr3-75738395-G-A
• rs193921040
• NM_001290208.3:c.1228C>T

Variant summary

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

The NM_001290208.3(ZNF717):​c.1228C>T​(p.Leu410Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L410V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 48)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF717 NM_001290208.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 0 publications found

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

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=0.2183978).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF717	NM_001290208.3	MANE Select	c.1228C>T	p.Leu410Phe	missense	Exon 5 of 5	NP_001277137.1	Q9BY31
	ZNF717	NM_001128223.3		c.1228C>T	p.Leu410Phe	missense	Exon 5 of 5	NP_001121695.1	Q9BY31
	ZNF717	NM_001290209.3		c.1078C>T	p.Leu360Phe	missense	Exon 5 of 5	NP_001277138.1	C9JVC3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF717	ENST00000652011.2	MANE Select	c.1228C>T	p.Leu410Phe	missense	Exon 5 of 5	ENSP00000498738.1	Q9BY31
	ZNF717	ENST00000850935.1		c.1330C>T	p.Leu444Phe	missense	Exon 6 of 6	ENSP00000521016.1	A0ABJ7H8Q2
	ZNF717	ENST00000852299.1		c.1228C>T	p.Leu410Phe	missense	Exon 5 of 5	ENSP00000522358.1

Frequencies

GnomAD3 genomes Cov.: 48

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386714 Hom.: 0 Cov.: 75 AF XY: 0.00000146 AC XY: 1 AN XY: 683954

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31266

American (AMR) AF: 0.00 AC: 0 AN: 34868

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24712

East Asian (EAS) AF: 0.00 AC: 0 AN: 35134

South Asian (SAS) AF: 0.00 AC: 0 AN: 78490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49066

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.00000187 AC: 2 AN: 1070276

Other (OTH) AF: 0.00 AC: 0 AN: 57248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 48

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	1.0
Eigen	Benign	0.0083
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.92	T
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.047	D
Vest4		0.097
MVP		0.13
ClinPred		0.92	D
GERP RS		1.7
gMVP		0.0019
Mutation Taster		=100/0	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: rs193921040; hg19: chr3-75787546;