4-166003554-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012464.5(TLL1):c.796G>C(p.Glu266Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLL1 NM_012464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLL1	NM_012464.5	c.796G>C	p.Glu266Gln	missense_variant	6/21	ENST00000061240.7
TLL1	NM_001204760.2	c.796G>C	p.Glu266Gln	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7	c.796G>C	p.Glu266Gln	missense_variant	6/21	1	NM_012464.5	P1
TLL1	ENST00000507499.5	c.796G>C	p.Glu266Gln	missense_variant	6/22	1
TLL1	ENST00000513213.5	c.796G>C	p.Glu266Gln	missense_variant	6/10	1
TLL1	ENST00000509505.5	c.*441G>C		3_prime_UTR_variant, NMD_transcript_variant	6/21	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.796G>C (p.E266Q) alteration is located in exon 6 (coding exon 6) of the TLL1 gene. This alteration results from a G to C substitution at nucleotide position 796, causing the glutamic acid (E) at amino acid position 266 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.0018	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.4	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.0	N;N;N
REVEL	Benign	0.22
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.091	T;T;T
Polyphen		0.48	P;P;.
Vest4		0.46
MutPred		0.57		Loss of catalytic residue at E266 (P = 0.0355);Loss of catalytic residue at E266 (P = 0.0355);Loss of catalytic residue at E266 (P = 0.0355);
MVP		0.72
MPC		0.26
ClinPred		0.90	D
GERP RS		5.3
Varity_R		0.59
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166924706;