2-179446666-C-T

Position:

• chr2-179446666-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152520.6(ZNF385B):​c.820G>A​(p.Ala274Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZNF385B NM_152520.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.218

Genes affected

ZNF385B (HGNC:26332): (zinc finger protein 385B) Enables p53 binding activity. Involved in intrinsic apoptotic signaling pathway by p53 class mediator. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.095434666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZNF385B	NM_152520.6	c.820G>A	p.Ala274Thr	missense_variant	7/10	ENST00000410066.7	NP_689733.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZNF385B	ENST00000410066.7	c.820G>A	p.Ala274Thr	missense_variant	7/10	1	NM_152520.6	ENSP00000386845	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

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

Oct 26, 2022

The c.775G>A (p.A259T) alteration is located in exon 7 (coding exon 5) of the ZNF385B gene. This alteration results from a G to A substitution at nucleotide position 775, causing the alanine (A) at amino acid position 259 to be replaced by a threonine (T). 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
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0048	.;.;.;.;T;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.74	T;.;T;T;T;T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.095	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;.;.;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.50	.;N;N;N;.;N
REVEL	Benign	0.059
Sift	Benign	0.42	.;T;T;T;.;T
Sift4G	Benign	0.50	.;T;T;T;.;T
Polyphen		0.013, 0.0040	.;.;B;.;B;.
Vest4		0.094, 0.095
MutPred		0.18		.;.;.;.;Gain of glycosylation at A259 (P = 2e-04);.;
MVP		0.099
MPC		0.19
ClinPred		0.10	T
GERP RS		5.0
Varity_R		0.040
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775577501; hg19: chr2-180311393;