NM_001316979.2:c.1075G>C

Variant names:

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

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>C​(p.Ala359Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000311 in 1,287,640 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A359T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: ZBTB45 NM_001316979.2 missense
• Clinical Significance: Not reported in ClinVar
• 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=0.053079367).

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>C	p.Ala359Pro	missense	Exon 2 of 3	NP_001303908.1	Q96K62
	ZBTB45	NM_001316978.2		c.1075G>C	p.Ala359Pro	missense	Exon 2 of 3	NP_001303907.1	Q96K62
	ZBTB45	NM_001316981.2		c.1075G>C	p.Ala359Pro	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>C	p.Ala359Pro	missense	Exon 2 of 3	ENSP00000469089.1	Q96K62
	ZBTB45	ENST00000354590.7	TSL:1	c.1075G>C	p.Ala359Pro	missense	Exon 2 of 3	ENSP00000346603.2	Q96K62
	ZBTB45	ENST00000869555.1		c.1075G>C	p.Ala359Pro	missense	Exon 2 of 4	ENSP00000539614.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000311 AC: 4 AN: 1287640 Hom.: 0 Cov.: 33 AF XY: 0.00000473 AC XY: 3 AN XY: 634398

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

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

American (AMR) AF: 0.00 AC: 0 AN: 34902

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

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 76752

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3704

European-Non Finnish (NFE) AF: 0.00000298 AC: 3 AN: 1007606

Other (OTH) AF: 0.00 AC: 0 AN: 50176

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000265607), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.036
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PhyloP100		-3.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.0070
Sift	Benign	0.90	T
Sift4G	Benign	0.38	T
Polyphen		0.41	B
Vest4		0.18
MutPred		0.21		Gain of glycosylation at A359 (P = 0.0012)
MVP		0.17
MPC		0.47
ClinPred		0.12	T
GERP RS		-6.3
Varity_R		0.056
gMVP		0.18
Mutation Taster		=93/7	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; COSMIC: COSV105027082; COSMIC: COSV105027082;