NM_001130144.3:c.100_105dupCTGCTG

Variant names:

• chr11-65557854-C-CCAGCAG
• rs71036212
• NM_001130144.3:c.100_105dupCTGCTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3 BP6 BA1

The NM_001130144.3(LTBP3):​c.100_105dupCTGCTG​(p.Leu34_Leu35dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,318,248 control chromosomes in the GnomAD database, including 7,553 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.12 (1439 hom., cov: 27)
  • Exomes 𝑓: 0.16 (6114 hom.)
• Consequence: LTBP3 NM_001130144.3 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.342
• Publications: 4 publications found

Genes affected

LTBP3 (HGNC:6716): (latent transforming growth factor beta binding protein 3) The protein encoded by this gene forms a complex with transforming growth factor beta (TGF-beta) proteins and may be involved in their subcellular localization. Activation of this complex requires removal of the encoded binding protein. This protein also may play a structural role in the extracellular matrix. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2010]

LTBP3 Gene-Disease associations (from GenCC):

• brachyolmia-amelogenesis imperfecta syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• geleophysic dysplasia 3

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• Acromicric dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• geleophysic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001130144.3
• BP6: Variant 11-65557854-C-CCAGCAG is Benign according to our data. Variant chr11-65557854-C-CCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 403062.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130144.3. 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
	LTBP3	NM_001130144.3	MANE Select	c.100_105dupCTGCTG	p.Leu34_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	NP_001123616.1
	LTBP3	NM_021070.4		c.100_105dupCTGCTG	p.Leu34_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	NP_066548.2
	LTBP3	NM_001164266.1		c.-248_-243dupCTGCTG		5_prime_UTR	Exon 1 of 27	NP_001157738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP3	ENST00000301873.11	TSL:2 MANE Select	c.100_105dupCTGCTG	p.Leu34_Leu35dup	conservative_inframe_insertion	Exon 1 of 28	ENSP00000301873.5
	LTBP3	ENST00000322147.8	TSL:1	c.100_105dupCTGCTG	p.Leu34_Leu35dup	conservative_inframe_insertion	Exon 1 of 27	ENSP00000326647.4
	LTBP3	ENST00000528516.5	TSL:1	n.100_105dupCTGCTG		non_coding_transcript_exon	Exon 1 of 27	ENSP00000432350.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18558 AN: 149128 Hom.: 1441 Cov.: 27

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.0934

Gnomad FIN AF: 0.0948

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.181

Gnomad OTH AF: 0.123

GnomAD2 exomes AF: 0.0772 AC: 2549 AN: 33030 AF XY: 0.0816

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.0534

Gnomad ASJ exome AF: 0.0733

Gnomad EAS exome AF: 0.00402

Gnomad FIN exome AF: 0.0637

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0850

GnomAD4 exome AF: 0.158 AC: 184412 AN: 1169030 Hom.: 6114 Cov.: 26 AF XY: 0.157 AC XY: 89622 AN XY: 571230

African (AFR) AF: 0.0412 AC: 987 AN: 23974

American (AMR) AF: 0.114 AC: 2191 AN: 19186

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 2189 AN: 17666

East Asian (EAS) AF: 0.0536 AC: 1363 AN: 25424

South Asian (SAS) AF: 0.0804 AC: 3856 AN: 47976

European-Finnish (FIN) AF: 0.0926 AC: 2447 AN: 26426

Middle Eastern (MID) AF: 0.149 AC: 567 AN: 3816

European-Non Finnish (NFE) AF: 0.171 AC: 164208 AN: 957742

Other (OTH) AF: 0.141 AC: 6604 AN: 46820

GnomAD4 genome AF: 0.124 AC: 18545 AN: 149218 Hom.: 1439 Cov.: 27 AF XY: 0.118 AC XY: 8597 AN XY: 72830

African (AFR) AF: 0.0497 AC: 2038 AN: 41026

American (AMR) AF: 0.124 AC: 1859 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 489 AN: 3424

East Asian (EAS) AF: 0.0282 AC: 144 AN: 5110

South Asian (SAS) AF: 0.0933 AC: 446 AN: 4782

European-Finnish (FIN) AF: 0.0948 AC: 918 AN: 9684

Middle Eastern (MID) AF: 0.206 AC: 59 AN: 286

European-Non Finnish (NFE) AF: 0.181 AC: 12099 AN: 66904

Other (OTH) AF: 0.121 AC: 248 AN: 2054

Alfa AF: 0.0364 Hom.: 40

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Brachyolmia-amelogenesis imperfecta syndrome (1)
-	1	-	Brachyolmia-amelogenesis imperfecta syndrome;C4540511:Geleophysic dysplasia 3 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=84/16	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs71036212; hg19: chr11-65325325; COSMIC: COSV57239654; COSMIC: COSV57239654;