4-166038667-G-T

Variant names:

• chr4-166038667-G-T
• rs954709
• NM_012464.5:c.1159-672G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012464.5(TLL1):​c.1159-672G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 152,070 control chromosomes in the GnomAD database, including 2,130 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 0.15 (2130 hom., cov: 33)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.523
• Publications: 5 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 (AFR) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLL1	NM_012464.5	c.1159-672G>T		intron_variant	Intron 9 of 20	ENST00000061240.7	NP_036596.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.1159-672G>T		intron_variant	Intron 9 of 20	1	NM_012464.5	ENSP00000061240.2
TLL1	ENST00000507499.5	c.1159-672G>T		intron_variant	Intron 9 of 21	1		ENSP00000426082.1
TLL1	ENST00000509505.5	n.*804-672G>T		intron_variant	Intron 9 of 20	1		ENSP00000422692.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23095 AN: 151952 Hom.: 2131 Cov.: 33

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.0616

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.152 AC: 23114 AN: 152070 Hom.: 2130 Cov.: 33 AF XY: 0.152 AC XY: 11312 AN XY: 74312

African (AFR) AF: 0.260 AC: 10783 AN: 41498

American (AMR) AF: 0.108 AC: 1656 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0908 AC: 315 AN: 3468

East Asian (EAS) AF: 0.0613 AC: 318 AN: 5186

South Asian (SAS) AF: 0.152 AC: 733 AN: 4818

European-Finnish (FIN) AF: 0.148 AC: 1563 AN: 10568

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7279 AN: 67950

Other (OTH) AF: 0.130 AC: 275 AN: 2110

Alfa AF: 0.0749 Hom.: 147

Bravo AF: 0.155

Asia WGS AF: 0.101 AC: 351 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	1.6
DANN	Benign	0.34
PhyloP100		0.52
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: rs954709; hg19: chr4-166959819;