rs10880

Variant names:

• chr19-40622404-C-G
• rs10880
• NM_001042545.2:c.3221C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-40622404-C-G
• chr19-40622404-C-T

Variant summary

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

The NM_001042545.2(LTBP4):​c.3221C>G​(p.Thr1074Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1074K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: LTBP4 NM_001042545.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.152
• 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	NM_001042545.2	MANE Select	c.3221C>G	p.Thr1074Arg	missense	Exon 23 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.3422C>G	p.Thr1141Arg	missense	Exon 26 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.3311C>G	p.Thr1104Arg	missense	Exon 26 of 33	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000396819.8	TSL:1 MANE Select	c.3221C>G	p.Thr1074Arg	missense	Exon 23 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.3422C>G	p.Thr1141Arg	missense	Exon 26 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.3311C>G	p.Thr1104Arg	missense	Exon 26 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371886 Hom.: 0 Cov.: 36 AF XY: 0.00000149 AC XY: 1 AN XY: 671214

African (AFR) AF: 0.00 AC: 0 AN: 31716

American (AMR) AF: 0.00 AC: 0 AN: 35330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22706

East Asian (EAS) AF: 0.00 AC: 0 AN: 36324

South Asian (SAS) AF: 0.00 AC: 0 AN: 74348

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5480

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060868

Other (OTH) AF: 0.00 AC: 0 AN: 56726

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Benign	0.81
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.098	T
MetaSVM	Benign	-0.85	T
PhyloP100		0.15
PrimateAI	Uncertain	0.64	T
REVEL	Benign	0.23
Sift4G	Benign	0.54	T
Polyphen		0.39	B
Vest4		0.30
MutPred		0.27		Loss of glycosylation at T1141 (P = 0.0126)
MVP		0.26
MPC		0.39
ClinPred		0.19	T
GERP RS		3.8
Varity_R		0.074
gMVP		0.47
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.25		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10880; hg19: chr19-41128309;