chr11-66822606-T-G

Variant names:

• chr11-66822606-T-G
• rs1449401018
• NM_001302084.2:c.1006T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001302084.2(TOP6BL):​c.1006T>G​(p.Ser336Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,400,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S336P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: TOP6BL NM_001302084.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• hydatidiform mole, recurrent, 4

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3214109).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302084.2. 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
	TOP6BL	NM_001302084.2	MANE Select	c.1006T>G	p.Ser336Ala	missense	Exon 11 of 15	NP_001289013.1	Q8N6T0-6
	TOP6BL	NM_024650.4		c.1354T>G	p.Ser452Ala	missense	Exon 13 of 17	NP_078926.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TOP6BL	ENST00000540737.7	TSL:2 MANE Select	c.1006T>G	p.Ser336Ala	missense	Exon 11 of 15	ENSP00000444319.1	Q8N6T0-6
	TOP6BL	ENST00000525449.6	TSL:1	c.993+842T>G		intron	N/A	ENSP00000434648.2	A0A140TA08
	TOP6BL	ENST00000525908.6	TSL:2	c.1354T>G	p.Ser452Ala	missense	Exon 13 of 17	ENSP00000432039.3	A0A2U3TZP7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1400868 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 691030

African (AFR) AF: 0.00 AC: 0 AN: 31638

American (AMR) AF: 0.00 AC: 0 AN: 35810

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25202

East Asian (EAS) AF: 0.00 AC: 0 AN: 35828

South Asian (SAS) AF: 0.00 AC: 0 AN: 79256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1079560

Other (OTH) AF: 0.00 AC: 0 AN: 58246

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.069	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.49	T
PhyloP100		1.5
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.28
MVP		0.32
MPC		0.16
ClinPred		0.94	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.055
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs1449401018; hg19: chr11-66590077;