19-58514281-A-G

Variant names:

• chr19-58514281-A-G
• NM_001316979.2:c.1309T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001316979.2(ZBTB45):​c.1309T>C​(p.Trp437Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • 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: 1.08

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZBTB45	NM_001316979.2	c.1309T>C	p.Trp437Arg	missense_variant	Exon 3 of 3	ENST00000594051.6	NP_001303908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZBTB45	ENST00000594051.6	c.1309T>C	p.Trp437Arg	missense_variant	Exon 3 of 3	2	NM_001316979.2	ENSP00000469089.1
ZBTB45	ENST00000354590.7	c.1309T>C	p.Trp437Arg	missense_variant	Exon 3 of 3	1		ENSP00000346603.2
ZBTB45	ENST00000600990.1	c.1309T>C	p.Trp437Arg	missense_variant	Exon 3 of 3	5		ENSP00000473072.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455964 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 723420

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 12, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1309T>C (p.W437R) alteration is located in exon 3 (coding exon 2) of the ZBTB45 gene. This alteration results from a T to C substitution at nucleotide position 1309, causing the tryptophan (W) at amino acid position 437 to be replaced by an arginine (R). 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	Pathogenic	0.96
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	.;.;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.75	D;D;D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.77	N;N;N
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.3	D;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.028	D;.;.
Sift4G	Uncertain	0.0060	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.64
MutPred		0.71		Gain of disorder (P = 0.0353);Gain of disorder (P = 0.0353);Gain of disorder (P = 0.0353);
MVP		0.49
MPC		2.3
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.67
gMVP		0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-59025648;