1-246987415-A-C

Position:

• chr1-246987415-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000339986.8(ZNF695):​c.1100T>G​(p.Leu367Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF695 ENST00000339986.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.29

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF695	NM_020394.5	c.1100T>G	p.Leu367Arg	missense_variant	4/4	ENST00000339986.8	NP_065127.5
ZNF695	NM_001204221.2	c.390+710T>G		intron_variant			NP_001191150.2
ZNF695	NR_037892.2	n.543+706T>G		intron_variant
ZNF670-ZNF695	NR_037894.2	n.573+706T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF695	ENST00000339986.8	c.1100T>G	p.Leu367Arg	missense_variant	4/4	1	NM_020394.5	ENSP00000341236.7
ZNF670-ZNF695	ENST00000465049.6	n.358+706T>G		intron_variant		5		ENSP00000428213.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459866 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Mar 11, 2022

The c.1100T>G (p.L367R) alteration is located in exon 4 (coding exon 4) of the ZNF695 gene. This alteration results from a T to G substitution at nucleotide position 1100, causing the leucine (L) at amino acid position 367 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	Uncertain	0.46
BayesDel_addAF	Benign	-0.00051	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.000060	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.0038	T
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.40	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.28
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.76		Gain of MoRF binding (P = 0.0116);
MVP		0.40
MPC		0.33
ClinPred		0.99	D
GERP RS		0.64
Varity_R		0.79
gMVP		0.064

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-247150717;