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GeneBe

4-165873997-C-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The NM_012464.5(TLL1):c.93C>A(p.Leu31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,614,062 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0082 ( 21 hom., cov: 32)
Exomes 𝑓: 0.00082 ( 13 hom. )

Consequence

TLL1
NM_012464.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.185
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.54).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 4-165873997-C-A is Benign according to our data. Variant chr4-165873997-C-A is described in ClinVar as [Benign]. Clinvar id is 790557.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.185 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00819 (1247/152186) while in subpopulation AFR AF= 0.0285 (1182/41526). AF 95% confidence interval is 0.0271. There are 21 homozygotes in gnomad4. There are 571 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 1246 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TLL1NM_012464.5 linkuse as main transcriptc.93C>A p.Leu31= synonymous_variant 1/21 ENST00000061240.7
TLL1NM_001204760.2 linkuse as main transcriptc.93C>A p.Leu31= synonymous_variant 1/10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TLL1ENST00000061240.7 linkuse as main transcriptc.93C>A p.Leu31= synonymous_variant 1/211 NM_012464.5 P1O43897-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00819
AC:
1246
AN:
152068
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0285
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00340
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00478
GnomAD3 exomes
AF:
0.00231
AC:
577
AN:
250204
Hom.:
9
AF XY:
0.00165
AC XY:
223
AN XY:
135314
show subpopulations
Gnomad AFR exome
AF:
0.0316
Gnomad AMR exome
AF:
0.00116
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:
0.0000978
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.000824
AC:
1205
AN:
1461876
Hom.:
13
Cov.:
31
AF XY:
0.000705
AC XY:
513
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.0285
Gnomad4 AMR exome
AF:
0.00141
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000692
Gnomad4 OTH exome
AF:
0.00164
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00819
AC:
1247
AN:
152186
Hom.:
21
Cov.:
32
AF XY:
0.00767
AC XY:
571
AN XY:
74406
show subpopulations
Gnomad4 AFR
AF:
0.0285
Gnomad4 AMR
AF:
0.00340
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00473
Alfa
AF:
0.00367
Hom.:
2
Bravo
AF:
0.00908
Asia WGS
AF:
0.00115
AC:
4
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeDec 31, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.54
Cadd
Benign
9.0
Dann
Benign
0.61

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.

Other links and lift over

dbSNP: rs114412546; hg19: chr4-166795149; API