chr4-165972381-A-G

Variant names:

• chr4-165972381-A-G
• rs4485771
• NM_012464.5:c.170-17000A>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.170-17000A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,972 control chromosomes in the GnomAD database, including 26,629 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 0.56 (26629 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.344
• Publications: 4 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.697 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	NM_012464.5	MANE Select	c.170-17000A>G		intron	N/A	NP_036596.3
	TLL1	NM_001204760.2		c.170-17000A>G		intron	N/A	NP_001191689.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	ENST00000061240.7	TSL:1 MANE Select	c.170-17000A>G		intron	N/A	ENSP00000061240.2
	TLL1	ENST00000507499.5	TSL:1	c.170-17000A>G		intron	N/A	ENSP00000426082.1
	TLL1	ENST00000513213.5	TSL:1	c.170-17000A>G		intron	N/A	ENSP00000422937.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85662 AN: 151854 Hom.: 26621 Cov.: 32

Gnomad AFR AF: 0.300

Gnomad AMI AF: 0.695

Gnomad AMR AF: 0.708

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.356

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.694

Gnomad OTH AF: 0.595

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

GnomAD4 genome AF: 0.564 AC: 85706 AN: 151972 Hom.: 26629 Cov.: 32 AF XY: 0.563 AC XY: 41852 AN XY: 74298

African (AFR) AF: 0.300 AC: 12440 AN: 41430

American (AMR) AF: 0.708 AC: 10822 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2337 AN: 3462

East Asian (EAS) AF: 0.357 AC: 1841 AN: 5162

South Asian (SAS) AF: 0.509 AC: 2451 AN: 4818

European-Finnish (FIN) AF: 0.626 AC: 6615 AN: 10564

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.694 AC: 47127 AN: 67934

Other (OTH) AF: 0.593 AC: 1253 AN: 2112

Alfa AF: 0.642 Hom.: 61075

Bravo AF: 0.564

Asia WGS AF: 0.444 AC: 1544 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.43
DANN	Benign	0.51
PhyloP100		-0.34
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: rs4485771; hg19: chr4-166893533;