4-165992843-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012464.5(TLL1):c.320C>T(p.Ala107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TLL1 NM_012464.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2198768).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLL1	NM_012464.5	c.320C>T	p.Ala107Val	missense_variant	3/21	ENST00000061240.7
TLL1	NM_001204760.2	c.320C>T	p.Ala107Val	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7	c.320C>T	p.Ala107Val	missense_variant	3/21	1	NM_012464.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251104 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461134 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726860

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

May 06, 2022

The c.320C>T (p.A107V) alteration is located in exon 3 (coding exon 3) of the TLL1 gene. This alteration results from a C to T substitution at nucleotide position 320, causing the alanine (A) at amino acid position 107 to be replaced by a valine (V). 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	Benign	0.085
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.
Eigen	Benign	0.022
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D;D;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Benign	0.090
Sift	Benign	0.065	T;D;T;D
Sift4G	Uncertain	0.037	D;D;T;D
Polyphen		0.0010	B;B;.;.
Vest4		0.36
MutPred		0.35		Loss of ubiquitination at K104 (P = 0.0517);Loss of ubiquitination at K104 (P = 0.0517);Loss of ubiquitination at K104 (P = 0.0517);.;
MVP		0.77
MPC		0.25
ClinPred		0.49	T
GERP RS		4.7
Varity_R		0.13
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs776299665; hg19: chr4-166913995;