10-62399574-G-T

Variant names:

• chr10-62399574-G-T
• rs3758490
• NM_014951.3:c.1009G>T

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF365	NM_014951.3	MANE Select	c.1009G>T	p.Ala337Ser	missense	Exon 5 of 5	NP_055766.2
	ZNF365	NM_199450.3		c.924+10998G>T		intron	N/A	NP_955522.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZNF365	ENST00000395254.8	TSL:1 MANE Select	c.1009G>T	p.Ala337Ser	missense	Exon 5 of 5	ENSP00000378674.3
	ZNF365	ENST00000466727.1	TSL:1	n.372G>T		non_coding_transcript_exon	Exon 4 of 4
	ENSG00000285837	ENST00000647733.1		c.924+10998G>T		intron	N/A	ENSP00000502188.1

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

GnomAD2 exomes AF: 0.553 AC: 138925 AN: 251404 AF XY: 0.554

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 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

African (AFR) AF: 0.129 AC: 4333 AN: 33476

American (AMR) AF: 0.538 AC: 24076 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.537 AC: 14033 AN: 26136

East Asian (EAS) AF: 0.680 AC: 26986 AN: 39682

South Asian (SAS) AF: 0.449 AC: 38750 AN: 86256

European-Finnish (FIN) AF: 0.611 AC: 32645 AN: 53416

Middle Eastern (MID) AF: 0.485 AC: 2796 AN: 5768

European-Non Finnish (NFE) AF: 0.616 AC: 684507 AN: 1111990

Other (OTH) AF: 0.564 AC: 34056 AN: 60386

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

African (AFR) AF: 0.150 AC: 6220 AN: 41406

American (AMR) AF: 0.532 AC: 8114 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1849 AN: 3466

East Asian (EAS) AF: 0.691 AC: 3563 AN: 5160

South Asian (SAS) AF: 0.456 AC: 2179 AN: 4776

European-Finnish (FIN) AF: 0.604 AC: 6349 AN: 10508

Middle Eastern (MID) AF: 0.469 AC: 137 AN: 292

European-Non Finnish (NFE) AF: 0.615 AC: 41812 AN: 67942

Other (OTH) AF: 0.493 AC: 1040 AN: 2110

Alfa AF: 0.562 Hom.: 98052

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

May 05, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.14
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
Mutation Taster		=67/33	polymorphism

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

Other links and lift over

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