chr18-48029589-G-C

Position:

• chr18-48029589-G-C

Variant summary

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

The NM_001318841.2(ZBTB7C):​c.1531C>G​(p.Leu511Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ZBTB7C NM_001318841.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

Genes affected

ZBTB7C (HGNC:31700): (zinc finger and BTB domain containing 7C) 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 negative regulation of cell population proliferation. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2461302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZBTB7C	NM_001318841.2	c.1531C>G	p.Leu511Val	missense_variant	5/5	ENST00000590800.6	NP_001305770.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZBTB7C	ENST00000590800.6	c.1531C>G	p.Leu511Val	missense_variant	5/5	1	NM_001318841.2	ENSP00000467877	P1
ZBTB7C	ENST00000535628.6	c.1531C>G	p.Leu511Val	missense_variant	3/3	1		ENSP00000439781	P1
ZBTB7C	ENST00000586438.5	c.1531C>G	p.Leu511Val	missense_variant	3/3	1		ENSP00000468254	P1
ZBTB7C	ENST00000588982.5	c.1531C>G	p.Leu511Val	missense_variant	4/4	1		ENSP00000468782	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Mar 22, 2023

The c.1531C>G (p.L511V) alteration is located in exon 3 (coding exon 2) of the ZBTB7C gene. This alteration results from a C to G substitution at nucleotide position 1531, causing the leucine (L) at amino acid position 511 to be replaced by a valine (V). 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	Benign	0.11
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;T;T;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.72	.;.;.;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;L;L;L
MutationTaster	Benign	0.85	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.86	N;.;.;.
REVEL	Benign	0.045
Sift	Uncertain	0.0040	D;.;.;.
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.95	P;P;P;P
Vest4		0.23
MutPred		0.24		Gain of catalytic residue at L511 (P = 0.2522);Gain of catalytic residue at L511 (P = 0.2522);Gain of catalytic residue at L511 (P = 0.2522);Gain of catalytic residue at L511 (P = 0.2522);
MVP		0.13
MPC		0.81
ClinPred		0.67	D
GERP RS		4.5
Varity_R		0.19
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs543484162; hg19: chr18-45555960;