NM_012464.5:c.170-44948G>T

Variant names:

• chr4-165944433-G-T
• rs7691872
• NM_012464.5:c.170-44948G>T

Variant summary

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

The NM_012464.5(TLL1):​c.170-44948G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 152,104 control chromosomes in the GnomAD database, including 2,534 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 0.11 (2534 hom., cov: 32)
• Consequence: TLL1 NM_012464.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.352
• 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=-1.03).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.343 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.170-44948G>T		intron	N/A	NP_036596.3
	TLL1	NM_001204760.2		c.170-44948G>T		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.170-44948G>T		intron	N/A	ENSP00000061240.2
	TLL1	ENST00000507499.5	TSL:1	c.170-44948G>T		intron	N/A	ENSP00000426082.1
	TLL1	ENST00000513213.5	TSL:1	c.170-44948G>T		intron	N/A	ENSP00000422937.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17014 AN: 151986 Hom.: 2522 Cov.: 32

Gnomad AFR AF: 0.348

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0572

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.00603

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0185

Gnomad OTH AF: 0.0935

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

GnomAD4 genome AF: 0.112 AC: 17060 AN: 152104 Hom.: 2534 Cov.: 32 AF XY: 0.108 AC XY: 8029 AN XY: 74360

African (AFR) AF: 0.348 AC: 14428 AN: 41436

American (AMR) AF: 0.0570 AC: 871 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0278 AC: 134 AN: 4820

European-Finnish (FIN) AF: 0.00603 AC: 64 AN: 10614

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0185 AC: 1260 AN: 68008

Other (OTH) AF: 0.0920 AC: 194 AN: 2108

Alfa AF: 0.0411 Hom.: 463

Bravo AF: 0.126

Asia WGS AF: 0.0410 AC: 144 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.31
DANN	Benign	0.56
PhyloP100		-0.35
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: rs7691872; hg19: chr4-166865585;