rs12513380

Variant names:

• chr4-165909212-G-A
• rs12513380
• NM_012464.5:c.169+35139G>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.169+35139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 151,932 control chromosomes in the GnomAD database, including 4,091 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 0.22 (4091 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.184
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.394 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLL1	NM_012464.5	c.169+35139G>A		intron_variant	Intron 1 of 20	ENST00000061240.7	NP_036596.3
TLL1	NM_001204760.2	c.169+35139G>A		intron_variant	Intron 1 of 9		NP_001191689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.169+35139G>A		intron_variant	Intron 1 of 20	1	NM_012464.5	ENSP00000061240.2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32947 AN: 151814 Hom.: 4086 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.408

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.229

Gnomad OTH AF: 0.221

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

GnomAD4 genome AF: 0.217 AC: 32959 AN: 151932 Hom.: 4091 Cov.: 32 AF XY: 0.222 AC XY: 16455 AN XY: 74248

African (AFR) AF: 0.118 AC: 4885 AN: 41450

American (AMR) AF: 0.325 AC: 4968 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3470

East Asian (EAS) AF: 0.408 AC: 2108 AN: 5162

South Asian (SAS) AF: 0.409 AC: 1964 AN: 4802

European-Finnish (FIN) AF: 0.197 AC: 2081 AN: 10546

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.229 AC: 15533 AN: 67932

Other (OTH) AF: 0.219 AC: 461 AN: 2104

Alfa AF: 0.229 Hom.: 8246

Bravo AF: 0.222

Asia WGS AF: 0.376 AC: 1304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.47
DANN	Benign	0.56
PhyloP100		-0.18
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: rs12513380; hg19: chr4-166830364;