1-22501529-C-G

Variant names:

• chr1-22501529-C-G
• rs147421359
• NM_014870.4:c.869C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014870.4(ZBTB40):​c.869C>G​(p.Ser290*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB40 NM_014870.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.75
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB40	NM_014870.4	MANE Select	c.869C>G	p.Ser290*	stop_gained	Exon 4 of 18	NP_055685.3
	ZBTB40	NM_001083621.2		c.869C>G	p.Ser290*	stop_gained	Exon 5 of 19	NP_001077090.1	Q9NUA8-1
	ZBTB40	NM_001330398.2		c.832-4520C>G		intron	N/A	NP_001317327.1	F8WAI8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZBTB40	ENST00000375647.5	TSL:1 MANE Select	c.869C>G	p.Ser290*	stop_gained	Exon 4 of 18	ENSP00000364798.4	Q9NUA8-1
	ZBTB40	ENST00000374651.8	TSL:1	c.832-4520C>G		intron	N/A	ENSP00000363782.4	F8WAI8
	ZBTB40	ENST00000404138.5	TSL:5	c.869C>G	p.Ser290*	stop_gained	Exon 5 of 19	ENSP00000384527.1	Q9NUA8-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		2.8
Vest4		0.078
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=10/190	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -37

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147421359; hg19: chr1-22828022; COSMIC: COSV107483691;