4-165995090-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_012464.5(TLL1):c.544A>C(p.Met182Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M182V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLL1 NM_012464.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918
• PP5: Variant 4-165995090-A-C is Pathogenic according to our data. Variant chr4-165995090-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 4074.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLL1	NM_012464.5	c.544A>C	p.Met182Leu	missense_variant	5/21	ENST00000061240.7
TLL1	NM_001204760.2	c.544A>C	p.Met182Leu	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7	c.544A>C	p.Met182Leu	missense_variant	5/21	1	NM_012464.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Atrial septal defect 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	26
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T;.;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D
Polyphen		0.94	P;D;.;.
Vest4		0.66
MutPred		0.85		Loss of methylation at K187 (P = 0.0585);Loss of methylation at K187 (P = 0.0585);Loss of methylation at K187 (P = 0.0585);.;
MVP		0.76
MPC		0.80
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.94
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs137852951; hg19: chr4-166916242;