rs137852951

Variant names:

• chr4-165995090-A-C
• rs137852951
• NM_012464.5:c.544A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-165995090-A-C
• chr4-165995090-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 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
• 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: Uncertain_significance. The variant received 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 VariationId is 4074.Status of the report is no_assertion_criteria_provided, 0 stars.

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.544A>C	p.Met182Leu	missense	Exon 5 of 21	NP_036596.3
	TLL1	NM_001204760.2		c.544A>C	p.Met182Leu	missense	Exon 5 of 10	NP_001191689.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLL1	ENST00000061240.7	TSL:1 MANE Select	c.544A>C	p.Met182Leu	missense	Exon 5 of 21	ENSP00000061240.2
	TLL1	ENST00000507499.5	TSL:1	c.544A>C	p.Met182Leu	missense	Exon 5 of 22	ENSP00000426082.1
	TLL1	ENST00000513213.5	TSL:1	c.544A>C	p.Met182Leu	missense	Exon 5 of 10	ENSP00000422937.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Atrial septal defect 6 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.7	L
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.019	D
Polyphen		0.94	P
Vest4		0.66
MutPred		0.85		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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852951; hg19: chr4-166916242;