chr1-246987646-T-C

Position:

• chr1-246987646-T-C

Variant summary

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

The ENST00000339986.8(ZNF695):​c.869A>G​(p.His290Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF695 ENST00000339986.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.63

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]

ZNF695 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF695	NM_020394.5	c.869A>G	p.His290Arg	missense_variant	4/4	ENST00000339986.8	NP_065127.5
ZNF695	NM_001204221.2	c.390+479A>G		intron_variant			NP_001191150.2
ZNF695	NR_037892.2	n.543+475A>G		intron_variant
ZNF670-ZNF695	NR_037894.2	n.573+475A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF695	ENST00000339986.8	c.869A>G	p.His290Arg	missense_variant	4/4	1	NM_020394.5	ENSP00000341236.7
ZNF670-ZNF695	ENST00000465049.6	n.358+475A>G		intron_variant		5		ENSP00000428213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 12, 2023

The c.869A>G (p.H290R) alteration is located in exon 4 (coding exon 4) of the ZNF695 gene. This alteration results from a A to G substitution at nucleotide position 869, causing the histidine (H) at amino acid position 290 to be replaced by an arginine (R). 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	0.61
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.024
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.00060	N
LIST_S2	Benign	0.027	T
M_CAP	Benign	0.0035	T
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Benign	0.28
Sift	Uncertain	0.023	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.36
MutPred		0.75		Gain of MoRF binding (P = 0.0086);
MVP		0.36
MPC		0.30
ClinPred		0.98	D
GERP RS		-0.86
Varity_R		0.31
gMVP		0.026

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: rs1668894487; hg19: chr1-247150948;