19-58516511-G-A

Variant names:

• chr19-58516511-G-A
• rs781091082
• NM_001316979.2:c.1163C>T

Variant summary

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

The NM_001316979.2(ZBTB45):​c.1163C>T​(p.Pro388Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000013 (0 hom.)
• Consequence: ZBTB45 NM_001316979.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06

Genes affected

ZBTB45 (HGNC:23715): (zinc finger and BTB domain containing 45) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleoplasm. [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=0.1079357).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB45	NM_001316979.2	c.1163C>T	p.Pro388Leu	missense_variant	Exon 2 of 3	ENST00000594051.6	NP_001303908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB45	ENST00000594051.6	c.1163C>T	p.Pro388Leu	missense_variant	Exon 2 of 3	2	NM_001316979.2	ENSP00000469089.1
ZBTB45	ENST00000354590.7	c.1163C>T	p.Pro388Leu	missense_variant	Exon 2 of 3	1		ENSP00000346603.2
ZBTB45	ENST00000600990.1	c.1163C>T	p.Pro388Leu	missense_variant	Exon 2 of 3	5		ENSP00000473072.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1461260 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726956

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: 0.0000171

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

Nov 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1163C>T (p.P388L) alteration is located in exon 2 (coding exon 1) of the ZBTB45 gene. This alteration results from a C to T substitution at nucleotide position 1163, causing the proline (P) at amino acid position 388 to be replaced by a leucine (L). 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	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.015	T;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.66	.;.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.34	N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Benign	0.052
Sift	Benign	0.14	T;.;.
Sift4G	Uncertain	0.052	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.25
MutPred		0.27		Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);Loss of loop (P = 0.0203);
MVP		0.36
MPC		0.39
ClinPred		0.13	T
GERP RS		3.0
Varity_R		0.031
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs781091082; hg19: chr19-59027878;