rs12725956

Variant names:

• chr1-22461661-A-G
• rs12725956
• NM_014870.4:c.-70+9657A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014870.4(ZBTB40):​c.-70+9657A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 152,010 control chromosomes in the GnomAD database, including 7,714 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.29 (7714 hom., cov: 32)
• Consequence: ZBTB40 NM_014870.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 3 publications found

Genes affected

ZBTB40 (HGNC:29045): (zinc finger and BTB domain containing 40) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Involved in cellular response to DNA damage stimulus. Located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZBTB40 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014870.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB40	NM_014870.4	MANE Select	c.-70+9657A>G		intron	N/A	NP_055685.3
	ZBTB40	NM_001083621.2		c.-70+8715A>G		intron	N/A	NP_001077090.1
	ZBTB40	NM_001330398.2		c.-70+9657A>G		intron	N/A	NP_001317327.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB40	ENST00000375647.5	TSL:1 MANE Select	c.-70+9657A>G		intron	N/A	ENSP00000364798.4
	ZBTB40	ENST00000374651.8	TSL:1	c.-70+9657A>G		intron	N/A	ENSP00000363782.4
	ZBTB40	ENST00000404138.5	TSL:5	c.-70+8715A>G		intron	N/A	ENSP00000384527.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43758 AN: 151892 Hom.: 7709 Cov.: 32

Gnomad AFR AF: 0.0964

Gnomad AMI AF: 0.616

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.334

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.332

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43784 AN: 152010 Hom.: 7714 Cov.: 32 AF XY: 0.289 AC XY: 21498 AN XY: 74276

African (AFR) AF: 0.0966 AC: 4008 AN: 41510

American (AMR) AF: 0.254 AC: 3884 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1261 AN: 3470

East Asian (EAS) AF: 0.456 AC: 2350 AN: 5150

South Asian (SAS) AF: 0.429 AC: 2063 AN: 4812

European-Finnish (FIN) AF: 0.334 AC: 3516 AN: 10532

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.373 AC: 25315 AN: 67952

Other (OTH) AF: 0.338 AC: 714 AN: 2112

Alfa AF: 0.297 Hom.: 1000

Bravo AF: 0.273

Asia WGS AF: 0.435 AC: 1512 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.7
DANN	Benign	0.74
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

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: rs12725956; hg19: chr1-22788154; COSMIC: COSV65144888;