2-32947529-G-C

Variant names:

• chr2-32947529-G-C
• rs959419457
• NM_206943.4:c.205G>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.205G>C​(p.Ala69Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,398,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.421
• 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=0.051496148).

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.205G>C	p.Ala69Pro	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.205G>C	p.Ala69Pro	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.205G>C	p.Ala69Pro	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.205G>C	p.Ala69Pro	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.205G>C	p.Ala69Pro	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.0000992 AC: 15 AN: 151204 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: 0.000485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000107 AC: 5 AN: 46596 AF XY: 0.000178

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000905

Gnomad NFE exome AF: 0.0000539

Gnomad OTH exome AF: 0.000790

GnomAD4 exome AF: 0.000105 AC: 131 AN: 1247324 Hom.: 0 Cov.: 34 AF XY: 0.0000979 AC XY: 60 AN XY: 612708

African (AFR) AF: 0.00 AC: 0 AN: 24698

American (AMR) AF: 0.00 AC: 0 AN: 17518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20500

East Asian (EAS) AF: 0.00 AC: 0 AN: 26784

South Asian (SAS) AF: 0.0000160 AC: 1 AN: 62320

European-Finnish (FIN) AF: 0.00110 AC: 34 AN: 30966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3542

European-Non Finnish (NFE) AF: 0.0000910 AC: 92 AN: 1010454

Other (OTH) AF: 0.0000791 AC: 4 AN: 50542

GnomAD4 genome AF: 0.0000992 AC: 15 AN: 151204 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73812

African (AFR) AF: 0.00 AC: 0 AN: 41352

American (AMR) AF: 0.00 AC: 0 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000485 AC: 5 AN: 10316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67604

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000642

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	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.42
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.050	N
REVEL	Benign	0.16
Sift	Benign	0.21	T
Sift4G	Benign	0.25	T
Vest4		0.35
MutPred		0.28		Gain of glycosylation at A69 (P = 0.0207)
MVP		0.26
MPC		2.1
ClinPred		0.018	T
GERP RS		-0.071
Varity_R		0.095
gMVP		0.29
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs959419457; hg19: chr2-33172596;