10-62376285-G-A

Variant summary

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

The NM_014951.3(ZNF365):c.92G>A(p.Cys31Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ZNF365 NM_014951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.04

Genes affected

ZNF365 (HGNC:18194): (zinc finger protein 365) This gene encodes a zinc finger protein that may play a role in the repair of DNA damage and maintenance of genome stability. The N-terminal C2H2 zinc finger motif is required to form a protein complex with PARP1 and MRE11, which are known to be involved in the restart of stalled DNA replication forks. A mutation in this gene may be associated with breast cancer susceptibility. [provided by RefSeq, Mar 2020]

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, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZNF365	NM_014951.3	c.92G>A	p.Cys31Tyr	missense_variant	2/5	ENST00000395254.8
ZNF365	NM_199450.3	c.92G>A	p.Cys31Tyr	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZNF365	ENST00000395254.8	c.92G>A	p.Cys31Tyr	missense_variant	2/5	1	NM_014951.3	P1
ZNF365	ENST00000395255.7	c.92G>A	p.Cys31Tyr	missense_variant	2/5	1
ZNF365	ENST00000466727.1	n.106+1827G>A		intron_variant, non_coding_transcript_variant		1
ZNF365	ENST00000421210.1	c.92G>A	p.Cys31Tyr	missense_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 06, 2021

The c.92G>A (p.C31Y) alteration is located in exon 2 (coding exon 1) of the ZNF365 gene. This alteration results from a G to A substitution at nucleotide position 92, causing the cysteine (C) at amino acid position 31 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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.90	L;L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.95
MutPred		0.64		Gain of MoRF binding (P = 0.1158);Gain of MoRF binding (P = 0.1158);Gain of MoRF binding (P = 0.1158);Gain of MoRF binding (P = 0.1158);
MVP		0.96
MPC		1.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr10-64136044;