chr2-32947621-ACCG-A

Variant names:

• chr2-32947621-ACCG-A
• rs538338631
• NM_206943.4:c.316_318delCCG

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_206943.4(LTBP1):​c.316_318delCCG​(p.Pro106del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,162,572 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LTBP1 NM_206943.4 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.14
• Publications: 0 publications found

Genes affected

LTBP1 (HGNC:6714): (latent transforming growth factor beta binding protein 1) The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

LTBP1 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 2E

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_206943.4

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206943.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	NM_206943.4	MANE Select	c.316_318delCCG	p.Pro106del	conservative_inframe_deletion	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.316_318delCCG	p.Pro106del	conservative_inframe_deletion	Exon 1 of 34	NP_001381834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	ENST00000404816.7	TSL:5 MANE Select	c.316_318delCCG	p.Pro106del	conservative_inframe_deletion	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.316_318delCCG	p.Pro106del	conservative_inframe_deletion	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.316_318delCCG	p.Pro106del	conservative_inframe_deletion	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.0000333 AC: 5 AN: 150372 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000992

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000594

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00544 AC: 48 AN: 8816 AF XY: 0.00660

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.0164

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.0212

GnomAD4 exome AF: 0.000707 AC: 822 AN: 1162572 Hom.: 0 AF XY: 0.000839 AC XY: 475 AN XY: 565980

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000348 AC: 8 AN: 23016

American (AMR) AF: 0.00128 AC: 12 AN: 9368

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 23 AN: 15144

East Asian (EAS) AF: 0.000285 AC: 7 AN: 24580

South Asian (SAS) AF: 0.00519 AC: 225 AN: 43388

European-Finnish (FIN) AF: 0.00196 AC: 62 AN: 31644

Middle Eastern (MID) AF: 0.00147 AC: 5 AN: 3398

European-Non Finnish (NFE) AF: 0.000464 AC: 448 AN: 965286

Other (OTH) AF: 0.000685 AC: 32 AN: 46748

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000333 AC: 5 AN: 150372 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73388

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41126

American (AMR) AF: 0.00 AC: 0 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000992 AC: 1 AN: 10078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000594 AC: 4 AN: 67368

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000889026), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cutis laxa, autosomal recessive, type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs538338631; hg19: chr2-33172688;