chr2-32947527-C-T

Variant names:

• chr2-32947527-C-T
• rs1676364041
• NM_206943.4:c.203C>T

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.203C>T​(p.Ala68Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,232 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LTBP1 NM_206943.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.256
• 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=0.06010604).

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.203C>T	p.Ala68Val	missense	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.203C>T	p.Ala68Val	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.203C>T	p.Ala68Val	missense	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.203C>T	p.Ala68Val	missense	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.203C>T	p.Ala68Val	missense	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.00000661 AC: 1 AN: 151232 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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1248308 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 613280

African (AFR) AF: 0.00 AC: 0 AN: 24728

American (AMR) AF: 0.00 AC: 0 AN: 17612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20556

East Asian (EAS) AF: 0.00 AC: 0 AN: 26790

South Asian (SAS) AF: 0.00 AC: 0 AN: 62534

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1010938

Other (OTH) AF: 0.00 AC: 0 AN: 50586

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151232 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73816

African (AFR) AF: 0.00 AC: 0 AN: 41354

American (AMR) AF: 0.00 AC: 0 AN: 15198

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10334

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67608

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

Alfa AF: 0.00 Hom.: 0

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	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.26
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.15
Sift	Benign	0.14	T
Sift4G	Benign	0.27	T
Vest4		0.23
MutPred		0.25		Gain of catalytic residue at A68 (P = 0.0398)
MVP		0.22
MPC		1.8
ClinPred		0.060	T
GERP RS		-2.3
Varity_R		0.033
gMVP		0.22
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1676364041; hg19: chr2-33172594;