rs3758490

Positions:

• chr10-62399574-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_014951.3(ZNF365):​c.1009G>T​(p.Ala337Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 1,613,656 control chromosomes in the GnomAD database, including 280,486 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (20323 hom., cov: 31)
  • Exomes 𝑓: 0.59 (260163 hom.)
• Consequence: ZNF365 NM_014951.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.137

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 Benign. Variant got -16 ACMG points.

• BP6: Variant 10-62399574-G-T is Benign according to our data. Variant chr10-62399574-G-T is described in ClinVar as [Benign]. Clinvar id is 1282011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF365	NM_014951.3	c.1009G>T	p.Ala337Ser	missense_variant	5/5	ENST00000395254.8	NP_055766.2
ZNF365	NM_199450.3	c.924+10998G>T		intron_variant			NP_955522.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF365	ENST00000395254.8	c.1009G>T	p.Ala337Ser	missense_variant	5/5	1	NM_014951.3	ENSP00000378674.3
ENSG00000285837	ENST00000647733.1	c.924+10998G>T		intron_variant				ENSP00000502188.1
ZNF365	ENST00000395255.7	c.924+10998G>T		intron_variant		1		ENSP00000378675.3
ZNF365	ENST00000466727.1	n.372G>T		non_coding_transcript_exon_variant	4/4	1

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71828 AN: 151706 Hom.: 20314 Cov.: 31

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.629

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.690

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.465

Gnomad NFE AF: 0.615

Gnomad OTH AF: 0.491

GnomAD3 exomes AF: 0.553 AC: 138925 AN: 251404 Hom.: 40455 AF XY: 0.554 AC XY: 75266 AN XY: 135886

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.539

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.693

Gnomad SAS exome AF: 0.445

Gnomad FIN exome AF: 0.608

Gnomad NFE exome AF: 0.613

Gnomad OTH exome AF: 0.571

GnomAD4 exome AF: 0.590 AC: 862182 AN: 1461832 Hom.: 260163 Cov.: 66 AF XY: 0.587 AC XY: 427171 AN XY: 727210

Gnomad4 AFR exome AF: 0.129

Gnomad4 AMR exome AF: 0.538

Gnomad4 ASJ exome AF: 0.537

Gnomad4 EAS exome AF: 0.680

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.564

GnomAD4 genome AF: 0.473 AC: 71837 AN: 151824 Hom.: 20323 Cov.: 31 AF XY: 0.474 AC XY: 35137 AN XY: 74172

Gnomad4 AFR AF: 0.150

Gnomad4 AMR AF: 0.532

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.691

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.604

Gnomad4 NFE AF: 0.615

Gnomad4 OTH AF: 0.493

Alfa AF: 0.585 Hom.: 69211

Bravo AF: 0.453

TwinsUK AF: 0.612 AC: 2268

ALSPAC AF: 0.615 AC: 2370

ESP6500AA AF: 0.166 AC: 730

ESP6500EA AF: 0.610 AC: 5250

ExAC AF: 0.544 AC: 66081

Asia WGS AF: 0.509 AC: 1767 AN: 3478

EpiCase AF: 0.601

EpiControl AF: 0.602

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.010	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0000018	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.55	N
PROVEAN	Benign	0.48	N
REVEL	Benign	0.038
Sift	Benign	0.30	T
Sift4G	Benign	0.55	T
Polyphen		0.010	B
Vest4		0.012
ClinPred		0.0026	T
GERP RS		-1.9
Varity_R		0.045

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3758490; hg19: chr10-64159333; COSMIC: COSV67925197;