9-126880607-C-A

Position:

• chr9-126880607-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001099270.4(ZBTB34):​c.1208C>A​(p.Pro403His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB34 NM_001099270.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

Genes affected

ZBTB34 (HGNC:31446): (zinc finger and BTB domain containing 34) Predicted to enable DNA-binding transcription repressor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB34	NM_001099270.4	c.1208C>A	p.Pro403His	missense_variant	2/2	ENST00000319119.5	NP_001092740.2
ZBTB34	NM_001395198.1	c.1238C>A	p.Pro413His	missense_variant	3/3		NP_001382127.1
ZBTB34	XM_047423402.1	c.1238C>A	p.Pro413His	missense_variant	3/3		XP_047279358.1
ZBTB34	XM_011518699.4	c.1208C>A	p.Pro403His	missense_variant	2/2		XP_011517001.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB34	ENST00000319119.5	c.1208C>A	p.Pro403His	missense_variant	2/2	1	NM_001099270.4	ENSP00000317534.4
ZBTB34	ENST00000695642.1	c.1238C>A	p.Pro413His	missense_variant	3/3			ENSP00000512077.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

The c.1196C>A (p.P399H) alteration is located in exon 2 (coding exon 1) of the ZBTB34 gene. This alteration results from a C to A substitution at nucleotide position 1196, causing the proline (P) at amino acid position 399 to be replaced by a histidine (H). 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	1.0
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.046	D
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Uncertain	2.7	.;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.76		.;Gain of MoRF binding (P = 0.0452);
MVP		0.38
MPC		1.9
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.81

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: chr9-129642886;