4-166065042-G-A

Variant names:

• chr4-166065042-G-A
• rs6536942
• NM_012464.5:c.2008-641G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

TLL1 Gene-Disease associations (from GenCC):

• atrial septal defect 6

  Inheritance: AD Classification: LIMITED Submitted by: G2P, Ambry Genetics
• mitral valve prolapse

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	NM_012464.5	MANE Select	c.2008-641G>A		intron	N/A	NP_036596.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	ENST00000061240.7	TSL:1 MANE Select	c.2008-641G>A		intron	N/A	ENSP00000061240.2
	TLL1	ENST00000507499.5	TSL:1	c.2077-641G>A		intron	N/A	ENSP00000426082.1
	TLL1	ENST00000509505.5	TSL:1	n.*1653-641G>A		intron	N/A	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

African (AFR) AF: 0.982 AC: 40802 AN: 41546

American (AMR) AF: 0.934 AC: 14225 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.904 AC: 3138 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5162 AN: 5166

South Asian (SAS) AF: 0.981 AC: 4742 AN: 4832

European-Finnish (FIN) AF: 0.925 AC: 9821 AN: 10618

Middle Eastern (MID) AF: 0.935 AC: 275 AN: 294

European-Non Finnish (NFE) AF: 0.885 AC: 60144 AN: 67950

Other (OTH) AF: 0.926 AC: 1960 AN: 2116

Alfa AF: 0.902 Hom.: 113386

Bravo AF: 0.929

Asia WGS AF: 0.989 AC: 3434 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.26
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs6536942; hg19: chr4-166986194;