rs544553665

Variant names:

• chr2-32947592-C-G
• rs544553665
• NM_206943.4:c.268C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-32947592-C-G
• chr2-32947592-C-T

Variant summary

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

The NM_206943.4(LTBP1):​c.268C>G​(p.Pro90Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000739 in 1,312,086 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P90S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00
• 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=0.0055032372).

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.268C>G	p.Pro90Ala	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.268C>G	p.Pro90Ala	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.268C>G	p.Pro90Ala	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.268C>G	p.Pro90Ala	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.268C>G	p.Pro90Ala	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.000278 AC: 42 AN: 151042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000963

GnomAD2 exomes AF: 0.000131 AC: 1 AN: 7660 AF XY: 0.00

Gnomad AFR exome AF: 0.00746

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000457 AC: 53 AN: 1160936 Hom.: 0 Cov.: 34 AF XY: 0.0000248 AC XY: 14 AN XY: 564320

African (AFR) AF: 0.00219 AC: 50 AN: 22808

American (AMR) AF: 0.00 AC: 0 AN: 9360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15384

East Asian (EAS) AF: 0.00 AC: 0 AN: 25900

South Asian (SAS) AF: 0.0000237 AC: 1 AN: 42282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28268

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3172

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 967408

Other (OTH) AF: 0.0000431 AC: 2 AN: 46354

GnomAD4 genome AF: 0.000291 AC: 44 AN: 151150 Hom.: 0 Cov.: 32 AF XY: 0.000339 AC XY: 25 AN XY: 73844

African (AFR) AF: 0.000966 AC: 40 AN: 41414

American (AMR) AF: 0.000132 AC: 2 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10210

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67642

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000257

ClinVar

ClinVar submissions

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	0.064
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.10	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.49	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.0
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.18	N
REVEL	Benign	0.11
Sift	Benign	0.56	T
Sift4G	Benign	0.37	T
Vest4		0.084
MutPred		0.29		Loss of methylation at K89 (P = 0.0676)
MVP		0.10
MPC		1.7
ClinPred		0.0090	T
GERP RS		2.6
Varity_R		0.040
gMVP		0.26
Mutation Taster		=99/1	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: rs544553665; hg19: chr2-33172659;