chr8-28351797-C-A

Variant names:

• chr8-28351797-C-A
• rs150160656
• NM_018660.3:c.931G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_018660.3(ZNF395):​c.931G>T​(p.Asp311Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,398,182 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D311N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ZNF395 NM_018660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66
• Publications: 0 publications found

Genes affected

ZNF395 (HGNC:18737): (zinc finger protein 395) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Located in cytosol and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

FBXO16 (HGNC:13618): (F-box protein 16) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbx class. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF395	NM_018660.3	c.931G>T	p.Asp311Tyr	missense_variant	Exon 7 of 10	ENST00000344423.10	NP_061130.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF395	ENST00000344423.10	c.931G>T	p.Asp311Tyr	missense_variant	Exon 7 of 10	1	NM_018660.3	ENSP00000340494.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398182 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688622

African (AFR) AF: 0.00 AC: 0 AN: 32608

American (AMR) AF: 0.00 AC: 0 AN: 41312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22866

East Asian (EAS) AF: 0.00 AC: 0 AN: 39112

South Asian (SAS) AF: 0.00 AC: 0 AN: 78818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082332

Other (OTH) AF: 0.00 AC: 0 AN: 58106

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.931G>T (p.D311Y) alteration is located in exon 7 (coding exon 6) of the ZNF395 gene. This alteration results from a G to T substitution at nucleotide position 931, causing the aspartic acid (D) at amino acid position 311 to be replaced by a tyrosine (Y). 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	0.31
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	.;.;D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.7	M;M;M
PhyloP100		4.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.65
MutPred		0.49		Loss of disorder (P = 0.014);Loss of disorder (P = 0.014);Loss of disorder (P = 0.014);
MVP		0.59
MPC		1.1
ClinPred		1.0	D
GERP RS		5.0
PromoterAI		0.026	Neutral
Varity_R		0.79
gMVP		0.45
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150160656; hg19: chr8-28209314;