Variant 4-165873971-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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 (no stars).

Frequency

Genomes: 𝑓 0.068 ( 1151 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 1085 hom. )

Consequence

TLL1
NM_012464.5 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 2.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 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 no_assertion_criteria_provided, 0 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 linkuse as main transcript	c.67G>C	p.Gly23Arg	missense_variant	1/21	ENST00000061240.7
TLL1	NM_001204760.2 linkuse as main transcript	c.67G>C	p.Gly23Arg	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7 linkuse as main transcript	c.67G>C	p.Gly23Arg	missense_variant	1/21	1	NM_012464.5	P1	O43897-1

Frequencies

GnomAD3 genomes

AF:

0.0684

AC:

10404

AN:

152060

Hom.:

1143

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00640

AC XY:

4654

AN XY:

727236

show subpopulations

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.:

AF XY:

0.0668

AC XY:

4967

AN XY:

74398

show subpopulations

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.:

Bravo

AF:

0.0778

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.234

AC:

1029

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.0216

AC:

2624

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000981

EpiControl

AF:

0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TLL1-related disorder

Benign:1

Benign, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.071

T;.;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.58

T;T;T

MetaRNN

Benign

0.0047

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;L

MutationTaster

Benign

0.96

P;P;P

PrimateAI

Benign

0.37

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over