1-22501585-G-T

Position:

• chr1-22501585-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000375647.5(ZBTB40):​c.925G>T​(p.Val309Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V309L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZBTB40 ENST00000375647.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.14

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13455406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB40	NM_014870.4	c.925G>T	p.Val309Phe	missense_variant	4/18	ENST00000375647.5	NP_055685.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB40	ENST00000375647.5	c.925G>T	p.Val309Phe	missense_variant	4/18	1	NM_014870.4	ENSP00000364798.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Feb 22, 2023

The c.925G>T (p.V309F) alteration is located in exon 5 (coding exon 3) of the ZBTB40 gene. This alteration results from a G to T substitution at nucleotide position 925, causing the valine (V) at amino acid position 309 to be replaced by a phenylalanine (F). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.82	T;T;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.70	N;N;N
REVEL	Benign	0.079
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;T;D
Polyphen		0.84	P;.;P
Vest4		0.21
MutPred		0.24		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.34
MPC		0.15
ClinPred		0.83	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-22828078;