NM_206943.4:c.185A>G

Variant names:

• chr2-32947509-A-G
• rs906416981
• NM_206943.4:c.185A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_206943.4(LTBP1):​c.185A>G​(p.Tyr62Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000787 in 1,422,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.27
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.185A>G	p.Tyr62Cys	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.185A>G	p.Tyr62Cys	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.185A>G	p.Tyr62Cys	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.185A>G	p.Tyr62Cys	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.185A>G	p.Tyr62Cys	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.0000463 AC: 7 AN: 151236 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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000981 AC: 6 AN: 61172 AF XY: 0.0000278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000857

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000826 AC: 105 AN: 1271082 Hom.: 0 Cov.: 34 AF XY: 0.0000768 AC XY: 48 AN XY: 625078

African (AFR) AF: 0.00 AC: 0 AN: 25392

American (AMR) AF: 0.000240 AC: 5 AN: 20798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21728

East Asian (EAS) AF: 0.00 AC: 0 AN: 27028

South Asian (SAS) AF: 0.00 AC: 0 AN: 66742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3696

European-Non Finnish (NFE) AF: 0.0000949 AC: 97 AN: 1022138

Other (OTH) AF: 0.0000579 AC: 3 AN: 51818

GnomAD4 genome AF: 0.0000463 AC: 7 AN: 151346 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73956

African (AFR) AF: 0.00 AC: 0 AN: 41448

American (AMR) AF: 0.00 AC: 0 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3456

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10316

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67652

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.0000945

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	Uncertain	0.54
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.90	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.26	N
REVEL	Uncertain	0.48
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Vest4		0.60
MutPred		0.38		Loss of catalytic residue at Y62 (P = 0.0688)
MVP		0.49
MPC		2.2
ClinPred		0.091	T
GERP RS		2.0
Varity_R		0.089
gMVP		0.43
Mutation Taster		=93/7	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: rs906416981; hg19: chr2-33172576;