dbSNP rs369989753: TOP6BL:p.His474Gln (chr11-66843021-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001302084.2(TOP6BL):c.1422C>G(p.His474Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TOP6BL
NM_001302084.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Variant links:

Genes affected

TOP6BL (HGNC:26197): (TOP6B like initiator of meiotic double strand breaks) Predicted to be involved in meiotic DNA double-strand break formation and reciprocal meiotic recombination. Predicted to be located in chromosome. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

TOP6BL links:

RCE1 (HGNC:13721): (Ras converting CAAX endopeptidase 1) This gene encodes an integral membrane protein which is classified as a member of the metalloproteinase family. This enzyme is thought to function in the maintenance and processing of CAAX-type prenylated proteins. [provided by RefSeq, Jul 2008]

RCE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.08575338).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TOP6BL	NM_001302084.2 link	c.1422C>G	p.His474Gln	missense_variant	Exon 14 of 15	ENST00000540737.7	NP_001289013.1	Q8N6T0B4DXL1
TOP6BL	NM_024650.4 link	c.1773C>G	p.His591Gln	missense_variant	Exon 16 of 17		NP_078926.4	Q8N6T0-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C11orf80	ENST00000540737.7 link	c.1422C>G	p.His474Gln	missense_variant	Exon 14 of 15	2	NM_001302084.2	ENSP00000444319.1		B4DXL1
C11orf80	ENST00000525449.6 link	c.1344C>G	p.His448Gln	missense_variant	Exon 14 of 15	1		ENSP00000434648.2		A0A140TA08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000654

AC:

AN:

152882

Hom.:

AF XY:

0.00

AC XY:

AN XY:

83508

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000172

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401462

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691868

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.24e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.1

DANN

Benign

0.93

Eigen

Benign

-0.98

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0090

LIST_S2

Benign

0.46

T;T;T;T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.086

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

PROVEAN

Benign

-1.1

.;N;N;N;.;.;.

REVEL

Benign

0.022

Sift

Benign

0.11

.;T;T;T;.;.;.

Sift4G

Benign

0.17

.;.;T;T;.;T;T

Polyphen

0.062, 0.14

.;.;B;B;.;.;.

Vest4

0.14, 0.12, 0.14, 0.15

MVP

0.076

MPC

0.33

ClinPred

0.23

GERP RS

1.1

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over