NM_001316979.2:c.1075G>A

Variant names:

• chr19-58516599-C-T
• rs539670110
• NM_001316979.2:c.1075G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001316979.2(ZBTB45):​c.1075G>A​(p.Ala359Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000503 in 1,431,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: ZBTB45 NM_001316979.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.80
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033112198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001316979.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB45	NM_001316979.2	MANE Select	c.1075G>A	p.Ala359Thr	missense	Exon 2 of 3	NP_001303908.1	Q96K62
	ZBTB45	NM_001316978.2		c.1075G>A	p.Ala359Thr	missense	Exon 2 of 3	NP_001303907.1	Q96K62
	ZBTB45	NM_001316981.2		c.1075G>A	p.Ala359Thr	missense	Exon 2 of 3	NP_001303910.1	Q96K62

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB45	ENST00000594051.6	TSL:2 MANE Select	c.1075G>A	p.Ala359Thr	missense	Exon 2 of 3	ENSP00000469089.1	Q96K62
	ZBTB45	ENST00000354590.7	TSL:1	c.1075G>A	p.Ala359Thr	missense	Exon 2 of 3	ENSP00000346603.2	Q96K62
	ZBTB45	ENST00000869555.1		c.1075G>A	p.Ala359Thr	missense	Exon 2 of 4	ENSP00000539614.1

Frequencies

GnomAD3 genomes AF: 0.0000347 AC: 5 AN: 144012 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000303

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000535 AC: 10 AN: 186922 AF XY: 0.0000594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000622

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000241

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 67 AN: 1287640 Hom.: 0 Cov.: 33 AF XY: 0.0000552 AC XY: 35 AN XY: 634398

African (AFR) AF: 0.00 AC: 0 AN: 29362

American (AMR) AF: 0.0000860 AC: 3 AN: 34902

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19022

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30200

South Asian (SAS) AF: 0.000104 AC: 8 AN: 76752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35916

Middle Eastern (MID) AF: 0.000270 AC: 1 AN: 3704

European-Non Finnish (NFE) AF: 0.0000516 AC: 52 AN: 1007606

Other (OTH) AF: 0.0000199 AC: 1 AN: 50176

GnomAD4 genome AF: 0.0000347 AC: 5 AN: 144012 Hom.: 0 Cov.: 32 AF XY: 0.0000143 AC XY: 1 AN XY: 70008

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000257 AC: 1 AN: 38922

American (AMR) AF: 0.000138 AC: 2 AN: 14460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4566

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000303 AC: 2 AN: 66066

Other (OTH) AF: 0.00 AC: 0 AN: 1998

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000328985), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

ExAC AF: 0.0000167 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.063
DANN	Benign	0.89
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.14	N
PhyloP100		-3.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.0030
Sift	Benign	0.41	T
Sift4G	Benign	0.69	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.25		Gain of glycosylation at A359 (P = 0)
MVP		0.13
MPC		0.35
ClinPred		0.13	T
GERP RS		-6.3
Varity_R		0.034
gMVP		0.14
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs539670110; hg19: chr19-59027966;