4-165873987-G-C

Position:

• chr4-165873987-G-C

Variant summary

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

The ENST00000061240.7(TLL1):​c.83G>C​(p.Cys28Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: TLL1 ENST00000061240.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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=0.13742176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLL1	NM_012464.5	c.83G>C	p.Cys28Ser	missense_variant	1/21	ENST00000061240.7	NP_036596.3
TLL1	NM_001204760.2	c.83G>C	p.Cys28Ser	missense_variant	1/10		NP_001191689.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLL1	ENST00000061240.7	c.83G>C	p.Cys28Ser	missense_variant	1/21	1	NM_012464.5	ENSP00000061240	P1

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

Jan 10, 2023

The c.83G>C (p.C28S) alteration is located in exon 1 (coding exon 1) of the TLL1 gene. This alteration results from a G to C substitution at nucleotide position 83, causing the cysteine (C) at amino acid position 28 to be replaced by a serine (S). 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	0.072
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.48
DEOGEN2	Benign	0.041	T;.;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.53	T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;N
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.24	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.20
MutPred		0.60		Gain of phosphorylation at Y33 (P = 0.118);Gain of phosphorylation at Y33 (P = 0.118);Gain of phosphorylation at Y33 (P = 0.118);
MVP		0.24
MPC		0.31
ClinPred		0.34	T
GERP RS		2.3
Varity_R		0.15
gMVP		0.32

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-166795139;