rs1503298

Variant names:

• chr4-166048493-T-C
• rs1503298
• NM_012464.5:c.1524+5074T>C

Variant summary

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

The NM_012464.5(TLL1):​c.1524+5074T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,010 control chromosomes in the GnomAD database, including 19,334 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 0.49 (19334 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.826
• Publications: 7 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLL1	NM_012464.5	c.1524+5074T>C		intron_variant	Intron 12 of 20	ENST00000061240.7	NP_036596.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.1524+5074T>C		intron_variant	Intron 12 of 20	1	NM_012464.5	ENSP00000061240.2
TLL1	ENST00000507499.5	c.1593+4060T>C		intron_variant	Intron 13 of 21	1		ENSP00000426082.1
TLL1	ENST00000509505.5	n.*1169+5074T>C		intron_variant	Intron 12 of 20	1		ENSP00000422692.1

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74887 AN: 151892 Hom.: 19297 Cov.: 32

Gnomad AFR AF: 0.640

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.550

Gnomad EAS AF: 0.483

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.434

Gnomad MID AF: 0.439

Gnomad NFE AF: 0.436

Gnomad OTH AF: 0.495

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

GnomAD4 genome AF: 0.493 AC: 74969 AN: 152010 Hom.: 19334 Cov.: 32 AF XY: 0.492 AC XY: 36562 AN XY: 74294

African (AFR) AF: 0.640 AC: 26527 AN: 41462

American (AMR) AF: 0.386 AC: 5897 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.550 AC: 1907 AN: 3466

East Asian (EAS) AF: 0.483 AC: 2501 AN: 5174

South Asian (SAS) AF: 0.501 AC: 2413 AN: 4816

European-Finnish (FIN) AF: 0.434 AC: 4583 AN: 10548

Middle Eastern (MID) AF: 0.449 AC: 131 AN: 292

European-Non Finnish (NFE) AF: 0.436 AC: 29630 AN: 67952

Other (OTH) AF: 0.493 AC: 1039 AN: 2106

Alfa AF: 0.467 Hom.: 24787

Bravo AF: 0.494

Asia WGS AF: 0.477 AC: 1662 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	4.4
DANN	Benign	0.76
PhyloP100		-0.83
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: rs1503298; hg19: chr4-166969645;