NM_012464.5:c.1042+3442A>G

Variant names:

• chr4-166018002-A-G
• rs17689952
• NM_012464.5:c.1042+3442A>G

Variant summary

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

The NM_012464.5(TLL1):​c.1042+3442A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 148,928 control chromosomes in the GnomAD database, including 3,131 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 0.20 (3131 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.380
• Publications: 2 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 (EAS) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLL1	NM_012464.5	c.1042+3442A>G		intron_variant	Intron 8 of 20	ENST00000061240.7	NP_036596.3
TLL1	NM_001204760.2	c.1042+3442A>G		intron_variant	Intron 8 of 9		NP_001191689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.1042+3442A>G		intron_variant	Intron 8 of 20	1	NM_012464.5	ENSP00000061240.2
TLL1	ENST00000507499.5	c.1042+3442A>G		intron_variant	Intron 8 of 21	1		ENSP00000426082.1
TLL1	ENST00000513213.5	c.1042+3442A>G		intron_variant	Intron 8 of 9	1		ENSP00000422937.1
TLL1	ENST00000509505.5	n.*687+3442A>G		intron_variant	Intron 8 of 20	1		ENSP00000422692.1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29150 AN: 148810 Hom.: 3127 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.256

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.253

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.224

Gnomad NFE AF: 0.223

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.196 AC: 29164 AN: 148928 Hom.: 3131 Cov.: 32 AF XY: 0.198 AC XY: 14423 AN XY: 72822

African (AFR) AF: 0.109 AC: 4204 AN: 38618

American (AMR) AF: 0.184 AC: 2780 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 875 AN: 3464

East Asian (EAS) AF: 0.372 AC: 1921 AN: 5162

South Asian (SAS) AF: 0.298 AC: 1439 AN: 4822

European-Finnish (FIN) AF: 0.198 AC: 2104 AN: 10606

Middle Eastern (MID) AF: 0.231 AC: 66 AN: 286

European-Non Finnish (NFE) AF: 0.223 AC: 15117 AN: 67890

Other (OTH) AF: 0.205 AC: 425 AN: 2072

Alfa AF: 0.216 Hom.: 14345

Bravo AF: 0.185

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		0.38
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: rs17689952; hg19: chr4-166939154;