4-165873971-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_012464.5(TLL1):c.67G>C(p.Gly23Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,614,046 control chromosomes in the GnomAD database, including 2,236 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.068 (1151 hom., cov: 32)
  • Exomes 𝑓: 0.0073 (1085 hom.)
• Consequence: TLL1 NM_012464.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004659772).
• BP6: Variant 4-165873971-G-C is Benign according to our data. Variant chr4-165873971-G-C is described in ClinVar as [Benign]. Clinvar id is 3056763.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.23 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLL1	NM_012464.5	c.67G>C	p.Gly23Arg	missense_variant	1/21	ENST00000061240.7
TLL1	NM_001204760.2	c.67G>C	p.Gly23Arg	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7	c.67G>C	p.Gly23Arg	missense_variant	1/21	1	NM_012464.5	P1

Frequencies

GnomAD3 genomes AF: 0.0684 AC: 10404 AN: 152060 Hom.: 1143 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0516

GnomAD3 exomes AF: 0.0179 AC: 4485 AN: 250650 Hom.: 448 AF XY: 0.0131 AC XY: 1773 AN XY: 135500

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00240

Gnomad NFE exome AF: 0.000788

Gnomad OTH exome AF: 0.00945

GnomAD4 exome AF: 0.00726 AC: 10613 AN: 1461868 Hom.: 1085 Cov.: 31 AF XY: 0.00640 AC XY: 4654 AN XY: 727236

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.00383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000499

Gnomad4 FIN exome AF: 0.00212

Gnomad4 NFE exome AF: 0.000420

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0685 AC: 10422 AN: 152178 Hom.: 1151 Cov.: 32 AF XY: 0.0668 AC XY: 4967 AN XY: 74398

Gnomad4 AFR AF: 0.234

Gnomad4 AMR AF: 0.0306

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.0511

Alfa AF: 0.00420 Hom.: 29

Bravo AF: 0.0778

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.234 AC: 1029

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.0216 AC: 2624

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TLL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	16
Dann	Benign	0.71
DEOGEN2	Benign	0.071	T;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;L
MutationTaster	Benign	0.96	P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.062
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.18
MutPred		0.45		Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);Loss of sheet (P = 0.0063);
MPC		0.30
ClinPred		0.0065	T
GERP RS		2.4
Varity_R		0.11
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs72984287; hg19: chr4-166795123; COSMIC: COSV50261143; COSMIC: COSV50261143;