chr2-32947681-C-A

Variant names:

• chr2-32947681-C-A
• rs202228164
• NM_206943.4:c.357C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_206943.4(LTBP1):​c.357C>A​(p.His119Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,494,734 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: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (0 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.302
• Publications: 1 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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011304617).

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.357C>A	p.His119Gln	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.357C>A	p.His119Gln	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.357C>A	p.His119Gln	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.357C>A	p.His119Gln	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.357C>A	p.His119Gln	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.000455 AC: 69 AN: 151736 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000479

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000854

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000399 AC: 46 AN: 115158 AF XY: 0.000304

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: 0.000212

Gnomad NFE exome AF: 0.000932

Gnomad OTH exome AF: 0.000705

GnomAD4 exome AF: 0.000512 AC: 687 AN: 1342890 Hom.: 0 Cov.: 33 AF XY: 0.000500 AC XY: 332 AN XY: 664298

African (AFR) AF: 0.0000732 AC: 2 AN: 27338

American (AMR) AF: 0.0000332 AC: 1 AN: 30142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23320

East Asian (EAS) AF: 0.00 AC: 0 AN: 28958

South Asian (SAS) AF: 0.000162 AC: 12 AN: 74024

European-Finnish (FIN) AF: 0.000629 AC: 29 AN: 46090

Middle Eastern (MID) AF: 0.00192 AC: 10 AN: 5202

European-Non Finnish (NFE) AF: 0.000578 AC: 609 AN: 1052918

Other (OTH) AF: 0.000437 AC: 24 AN: 54898

GnomAD4 genome AF: 0.000454 AC: 69 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.000377 AC XY: 28 AN XY: 74232

African (AFR) AF: 0.0000723 AC: 3 AN: 41502

American (AMR) AF: 0.000131 AC: 2 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000479 AC: 5 AN: 10448

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000854 AC: 58 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000472 Hom.: 0

Bravo AF: 0.000378

ExAC AF: 0.000470 AC: 52

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.36	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.30
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.41	N
REVEL	Benign	0.15
Sift	Benign	0.90	T
Sift4G	Benign	0.68	T
Vest4		0.14
MutPred		0.23		Gain of sheet (P = 0.1945)
MVP		0.093
MPC		0.13
ClinPred		0.020	T
GERP RS		1.3
Varity_R		0.062
gMVP		0.17
Mutation Taster		=96/4	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: rs202228164; hg19: chr2-33172748;