4-165951384-C-A

Variant names:

• chr4-165951384-C-A
• rs6812849
• NM_012464.5:c.170-37997C>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.170-37997C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 151,980 control chromosomes in the GnomAD database, including 4,597 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 (4597 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25
• Publications: 13 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: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.459 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	NM_012464.5	MANE Select	c.170-37997C>A		intron	N/A	NP_036596.3
	TLL1	NM_001204760.2		c.170-37997C>A		intron	N/A	NP_001191689.1	O43897-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	ENST00000061240.7	TSL:1 MANE Select	c.170-37997C>A		intron	N/A	ENSP00000061240.2	O43897-1
	TLL1	ENST00000507499.5	TSL:1	c.170-37997C>A		intron	N/A	ENSP00000426082.1	E9PD25
	TLL1	ENST00000513213.5	TSL:1	c.170-37997C>A		intron	N/A	ENSP00000422937.1	O43897-2

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22343 AN: 151862 Hom.: 4571 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0727

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.0303

Gnomad FIN AF: 0.00510

Gnomad MID AF: 0.0732

Gnomad NFE AF: 0.0189

Gnomad OTH AF: 0.120

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

GnomAD4 genome AF: 0.148 AC: 22425 AN: 151980 Hom.: 4597 Cov.: 32 AF XY: 0.142 AC XY: 10578 AN XY: 74282

African (AFR) AF: 0.465 AC: 19250 AN: 41406

American (AMR) AF: 0.0726 AC: 1107 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3464

East Asian (EAS) AF: 0.0398 AC: 205 AN: 5148

South Asian (SAS) AF: 0.0297 AC: 143 AN: 4816

European-Finnish (FIN) AF: 0.00510 AC: 54 AN: 10594

Middle Eastern (MID) AF: 0.0719 AC: 21 AN: 292

European-Non Finnish (NFE) AF: 0.0189 AC: 1286 AN: 67986

Other (OTH) AF: 0.126 AC: 266 AN: 2108

Alfa AF: 0.0529 Hom.: 2708

Bravo AF: 0.165

Asia WGS AF: 0.0690 AC: 240 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.7
DANN	Benign	0.53
PhyloP100		1.3
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: rs6812849; hg19: chr4-166872536;