1-246987052-C-T

Variant names:

• chr1-246987052-C-T
• rs1668871580
• NM_020394.5:c.1463G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020394.5(ZNF695):​c.1463G>A​(p.Arg488Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: ZNF695 NM_020394.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.21

Genes affected

ZNF695 (HGNC:30954): (zinc finger protein 695) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF670-ZNF695 (HGNC:49200): (ZNF670-ZNF695 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring zinc finger protein 670 (ZNF670) and zinc finger protein 695 (ZNF695) genes on chromosome 1. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05547273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF695	NM_020394.5	c.1463G>A	p.Arg488Lys	missense_variant	Exon 4 of 4	ENST00000339986.8	NP_065127.5
ZNF695	NM_001204221.2	c.390+1073G>A		intron_variant	Intron 4 of 5		NP_001191150.2
ZNF695	NR_037892.2	n.543+1069G>A		intron_variant	Intron 4 of 5
ZNF670-ZNF695	NR_037894.2	n.573+1069G>A		intron_variant	Intron 4 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF695	ENST00000339986.8	c.1463G>A	p.Arg488Lys	missense_variant	Exon 4 of 4	1	NM_020394.5	ENSP00000341236.7
ZNF670-ZNF695	ENST00000465049.6	n.358+1069G>A		intron_variant	Intron 4 of 6	5		ENSP00000428213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1463G>A (p.R488K) alteration is located in exon 4 (coding exon 4) of the ZNF695 gene. This alteration results from a G to A substitution at nucleotide position 1463, causing the arginine (R) at amino acid position 488 to be replaced by a lysine (K). 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	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.000040	N
LIST_S2	Benign	0.031	T
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.31	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.035
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.0010	B
Vest4		0.14
MutPred		0.38		Gain of methylation at R488 (P = 0.0037);
MVP		0.030
MPC		0.040
ClinPred		0.17	T
GERP RS		-0.57
Varity_R		0.072
gMVP		0.013

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: rs1668871580; hg19: chr1-247150354;