19-58516735-T-C

Variant names:

• chr19-58516735-T-C
• rs2053503663
• NM_001316979.2:c.939A>G

Variant summary

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

The NM_001316979.2(ZBTB45):​c.939A>G​(p.Ile313Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,078 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: 6.9e-7 (0 hom.)
• Consequence: ZBTB45 NM_001316979.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.216

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=0.12941977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB45	NM_001316979.2	c.939A>G	p.Ile313Met	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.939A>G	p.Ile313Met	missense_variant	Exon 2 of 3	2	NM_001316979.2	ENSP00000469089.1
ZBTB45	ENST00000354590.7	c.939A>G	p.Ile313Met	missense_variant	Exon 2 of 3	1		ENSP00000346603.2
ZBTB45	ENST00000600990.1	c.939A>G	p.Ile313Met	missense_variant	Exon 2 of 3	5		ENSP00000473072.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458078 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725080

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: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.939A>G (p.I313M) alteration is located in exon 2 (coding exon 1) of the ZBTB45 gene. This alteration results from a A to G substitution at nucleotide position 939, causing the isoleucine (I) at amino acid position 313 to be replaced by a methionine (M). 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	0.21
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.026	T;T;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.63	.;.;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.22	N;.;.
REVEL	Benign	0.073
Sift	Benign	0.24	T;.;.
Sift4G	Benign	0.24	T;T;T
Polyphen		0.12	B;B;B
Vest4		0.14
MutPred		0.48		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.18
MPC		0.43
ClinPred		0.094	T
GERP RS		3.1
Varity_R		0.025
gMVP		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2053503663; hg19: chr19-59028102;