rs6536942

Positions:

• chr4-166065042-G-A
• chr4-166065042-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012464.5(TLL1):​c.2008-641G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 152,132 control chromosomes in the GnomAD database, including 65,552 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.93 (65552 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.361

Genes affected

TLL1 (HGNC:11843): (tolloid like 1) This gene encodes an astacin-like, zinc-dependent, metalloprotease that belongs to the peptidase M12A family. This protease processes procollagen C-propeptides, such as chordin, pro-biglycan and pro-lysyl oxidase. Studies in mice suggest that this gene plays multiple roles in the development of mammalian heart, and is essential for the formation of the interventricular septum. Allelic variants of this gene are associated with atrial septal defect type 6. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLL1	NM_012464.5	c.2008-641G>A		intron_variant		ENST00000061240.7	NP_036596.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.2008-641G>A		intron_variant		1	NM_012464.5	ENSP00000061240.2
TLL1	ENST00000507499.5	c.2077-641G>A		intron_variant		1		ENSP00000426082.1
TLL1	ENST00000509505.5	n.*1653-641G>A		intron_variant		1		ENSP00000422692.1

Frequencies

GnomAD3 genomes AF: 0.927 AC: 140949 AN: 152014 Hom.: 65492 Cov.: 32

Gnomad AFR AF: 0.982

Gnomad AMI AF: 0.878

Gnomad AMR AF: 0.934

Gnomad ASJ AF: 0.904

Gnomad EAS AF: 0.999

Gnomad SAS AF: 0.982

Gnomad FIN AF: 0.925

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.926

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.927 AC: 141068 AN: 152132 Hom.: 65552 Cov.: 32 AF XY: 0.932 AC XY: 69330 AN XY: 74358

Gnomad4 AFR AF: 0.982

Gnomad4 AMR AF: 0.934

Gnomad4 ASJ AF: 0.904

Gnomad4 EAS AF: 0.999

Gnomad4 SAS AF: 0.981

Gnomad4 FIN AF: 0.925

Gnomad4 NFE AF: 0.885

Gnomad4 OTH AF: 0.926

Alfa AF: 0.898 Hom.: 82050

Bravo AF: 0.929

Asia WGS AF: 0.989 AC: 3434 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.26

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: rs6536942; hg19: chr4-166986194;