rs946722995

Variant names:

• chr10-62388396-A-G
• rs946722995
• NM_014951.3:c.744A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_014951.3(ZNF365):​c.744A>G​(p.Glu248Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZNF365 NM_014951.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.003575
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04

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]

ENSG00000285837 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-62388396-A-G is Benign according to our data. Variant chr10-62388396-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3335602.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.04 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF365	NM_014951.3	c.744A>G	p.Glu248Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	ENST00000395254.8	NP_055766.2
ZNF365	NM_199450.3	c.744A>G	p.Glu248Glu	splice_region_variant, synonymous_variant	Exon 3 of 5		NP_955522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZNF365	ENST00000395254.8	c.744A>G	p.Glu248Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	1	NM_014951.3	ENSP00000378674.3
ENSG00000285837	ENST00000647733.1	c.744A>G	p.Glu248Glu	splice_region_variant, synonymous_variant	Exon 3 of 8			ENSP00000502188.1
ZNF365	ENST00000395255.7	c.744A>G	p.Glu248Glu	splice_region_variant, synonymous_variant	Exon 3 of 5	1		ENSP00000378675.3
ZNF365	ENST00000466727.1	n.107A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 51

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

May 29, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0036
dbscSNV1_RF	Benign	0.076
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: rs946722995; hg19: chr10-64148155;