chr2-32947736-G-C

Variant names:

• chr2-32947736-G-C
• rs749331550
• NM_206943.4:c.412G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_206943.4(LTBP1):​c.412G>C​(p.Val138Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000361 in 1,386,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.774
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045240402).

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.412G>C	p.Val138Leu	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.412G>C	p.Val138Leu	missense	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.412G>C	p.Val138Leu	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.412G>C	p.Val138Leu	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.412G>C	p.Val138Leu	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000361 AC: 5 AN: 1386458 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688906

African (AFR) AF: 0.00 AC: 0 AN: 28642

American (AMR) AF: 0.00 AC: 0 AN: 35360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24068

East Asian (EAS) AF: 0.00 AC: 0 AN: 31760

South Asian (SAS) AF: 0.00 AC: 0 AN: 77762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00000465 AC: 5 AN: 1076240

Other (OTH) AF: 0.00 AC: 0 AN: 56710

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.84
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.77
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.15
Sift	Benign	0.90	T
Sift4G	Benign	0.80	T
Vest4		0.056
MutPred		0.13		Loss of methylation at K133 (P = 0.0933)
MVP		0.043
MPC		0.13
ClinPred		0.052	T
GERP RS		3.1
Varity_R		0.075
gMVP		0.087
Mutation Taster		=97/3	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: rs749331550; hg19: chr2-33172803;