10-62376578-T-A

Position:

• chr10-62376578-T-A

Variant summary

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

The NM_014951.3(ZNF365):​c.385T>A​(p.Tyr129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZNF365 NM_014951.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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]

ENSG00000285837 (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
ZNF365	NM_014951.3	c.385T>A	p.Tyr129Asn	missense_variant	2/5	ENST00000395254.8	NP_055766.2
ZNF365	NM_199450.3	c.385T>A	p.Tyr129Asn	missense_variant	2/5		NP_955522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF365	ENST00000395254.8	c.385T>A	p.Tyr129Asn	missense_variant	2/5	1	NM_014951.3	ENSP00000378674.3
ENSG00000285837	ENST00000647733.1	c.385T>A	p.Tyr129Asn	missense_variant	2/8			ENSP00000502188.1
ZNF365	ENST00000395255.7	c.385T>A	p.Tyr129Asn	missense_variant	2/5	1		ENSP00000378675.3
ZNF365	ENST00000466727.1	n.106+2120T>A		intron_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Aug 20, 2024

The c.385T>A (p.Y129N) alteration is located in exon 2 (coding exon 1) of the ZNF365 gene. This alteration results from a T to A substitution at nucleotide position 385, causing the tyrosine (Y) at amino acid position 129 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T;.;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.8	L;L;L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.51	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.077	T;T;D
Polyphen		0.83	P;P;D
Vest4		0.67
MutPred		0.54		Loss of phosphorylation at Y129 (P = 0.0086);Loss of phosphorylation at Y129 (P = 0.0086);Loss of phosphorylation at Y129 (P = 0.0086);
MVP		0.67
MPC		1.0
ClinPred		0.77	D
GERP RS		5.6
Varity_R		0.091
gMVP		0.44

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: rs1839334490; hg19: chr10-64136337;