rs1555741927

Variant names:

• chr19-40622950-C-T
• rs1555741927
• NM_001042545.2:c.3485C>T

Variant summary

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

The NM_001042545.2(LTBP4):​c.3485C>T​(p.Ala1162Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A1162A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: LTBP4 NM_001042545.2 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

Genes affected

LTBP4 (HGNC:6717): (latent transforming growth factor beta binding protein 4) The protein encoded by this gene binds transforming growth factor beta (TGFB) as it is secreted and targeted to the extracellular matrix. TGFB is biologically latent after secretion and insertion into the extracellular matrix, and sheds TGFB and other proteins upon activation. Defects in this gene may be a cause of cutis laxa and severe pulmonary, gastrointestinal, and urinary abnormalities. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2010]

LTBP4 Gene-Disease associations (from GenCC):

• cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia

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_001042545.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.3485C>T	p.Ala1162Val	missense splice_region	Exon 24 of 30	NP_001036010.1
	LTBP4	NM_001042544.1		c.3686C>T	p.Ala1229Val	missense splice_region	Exon 27 of 33	NP_001036009.1
	LTBP4	NM_003573.2		c.3575C>T	p.Ala1192Val	missense splice_region	Exon 27 of 33	NP_003564.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.3485C>T	p.Ala1162Val	missense splice_region	Exon 24 of 30	ENSP00000380031.5
	LTBP4	ENST00000308370.11	TSL:1	c.3686C>T	p.Ala1229Val	missense splice_region	Exon 27 of 33	ENSP00000311905.8
	LTBP4	ENST00000204005.13	TSL:1	c.3575C>T	p.Ala1192Val	missense splice_region	Exon 27 of 33	ENSP00000204005.10

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1460966 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726766

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53198

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1111590

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152122 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74296

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.093
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	0.67	D
PhyloP100		1.4
PrimateAI	Uncertain	0.67	T
REVEL	Uncertain	0.60
Sift4G	Benign	0.38	T
Polyphen		1.0	D
Vest4		0.23
MutPred		0.73		Loss of disorder (P = 0.078)
MVP		0.43
MPC		0.34
ClinPred		0.87	D
GERP RS		2.0
Varity_R		0.073
gMVP		0.45
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1555741927; hg19: chr19-41128855;