4-165873677-T-C

Position:

• chr4-165873677-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_012464.5(TLL1):​c.-228T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.207 in 519,492 control chromosomes in the GnomAD database, including 16,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (7516 hom., cov: 32)
  • Exomes 𝑓: 0.18 (8816 hom.)
• Consequence: TLL1 NM_012464.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.948

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-165873677-T-C is Benign according to our data. Variant chr4-165873677-T-C is described in ClinVar as [Benign]. Clinvar id is 1240677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.511 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLL1	NM_012464.5	c.-228T>C		5_prime_UTR_variant	1/21	ENST00000061240.7
TLL1	NM_001204760.2	c.-228T>C		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLL1	ENST00000061240.7	c.-228T>C		5_prime_UTR_variant	1/21	1	NM_012464.5	P1
TLL1	ENST00000507499.5	c.-228T>C		5_prime_UTR_variant	1/22	1
TLL1	ENST00000509505.5	c.-228T>C		5_prime_UTR_variant, NMD_transcript_variant	1/21	1
TLL1	ENST00000504560.5			upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.263 AC: 39904 AN: 151988 Hom.: 7491 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.178

Gnomad EAS AF: 0.468

Gnomad SAS AF: 0.259

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.228

GnomAD4 exome AF: 0.183 AC: 67395 AN: 367388 Hom.: 8816 Cov.: 3 AF XY: 0.186 AC XY: 35642 AN XY: 191784

Gnomad4 AFR exome AF: 0.506

Gnomad4 AMR exome AF: 0.192

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.237

Gnomad4 FIN exome AF: 0.133

Gnomad4 NFE exome AF: 0.127

Gnomad4 OTH exome AF: 0.190

GnomAD4 genome AF: 0.263 AC: 39981 AN: 152104 Hom.: 7516 Cov.: 32 AF XY: 0.263 AC XY: 19544 AN XY: 74370

Gnomad4 AFR AF: 0.517

Gnomad4 AMR AF: 0.208

Gnomad4 ASJ AF: 0.178

Gnomad4 EAS AF: 0.468

Gnomad4 SAS AF: 0.257

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.233

Alfa AF: 0.155 Hom.: 1920

Bravo AF: 0.277

Asia WGS AF: 0.342 AC: 1186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	15
DANN	Benign	0.85

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: rs1460072; hg19: chr4-166794829;