ENST00000308370.11:c.146+36A>G

Variant names:

• chr19-40597416-A-G
• rs79235206
• ENST00000308370.11:c.146+36A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000308370.11(LTBP4):​c.146+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000606 in 1,478,074 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 30)
  • Exomes 𝑓: 0.00028 (5 hom.)
• Consequence: LTBP4 ENST00000308370.11 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45
• Publications: 1 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: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-40597416-A-G is Benign according to our data. Variant chr19-40597416-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1178562.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00341 (519/152126) while in subpopulation AFR AF = 0.0122 (506/41500). AF 95% confidence interval is 0.0113. There are 5 homozygotes in GnomAd4. There are 268 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000308370.11. 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_001042544.1		c.146+36A>G		intron	N/A	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.17-1781A>G		intron	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000308370.11	TSL:1	c.146+36A>G		intron	N/A	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.17-1781A>G		intron	N/A	ENSP00000204005.10	A0A0C4DH07
	LTBP4	ENST00000599016.5	TSL:3	n.17-1781A>G		intron	N/A	ENSP00000482179.1	A0A087WYX7

Frequencies

GnomAD3 genomes AF: 0.00341 AC: 518 AN: 152014 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.0122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

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: 0.0000294

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000373 AC: 34 AN: 91162 AF XY: 0.000214

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000279

Gnomad OTH exome AF: 0.000377

GnomAD4 exome AF: 0.000284 AC: 377 AN: 1325948 Hom.: 5 Cov.: 33 AF XY: 0.000250 AC XY: 163 AN XY: 651570

African (AFR) AF: 0.0116 AC: 316 AN: 27316

American (AMR) AF: 0.000347 AC: 10 AN: 28824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23140

East Asian (EAS) AF: 0.00 AC: 0 AN: 30594

South Asian (SAS) AF: 0.0000271 AC: 2 AN: 73812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33870

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5516

European-Non Finnish (NFE) AF: 0.0000115 AC: 12 AN: 1047722

Other (OTH) AF: 0.000653 AC: 36 AN: 55154

GnomAD4 genome AF: 0.00341 AC: 519 AN: 152126 Hom.: 5 Cov.: 30 AF XY: 0.00360 AC XY: 268 AN XY: 74382

African (AFR) AF: 0.0122 AC: 506 AN: 41500

American (AMR) AF: 0.000654 AC: 10 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67994

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.00262 Hom.: 0

Bravo AF: 0.00449

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.2
DANN	Benign	0.41
PhyloP100		-1.4
PromoterAI		0.045	Neutral

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: rs79235206; hg19: chr19-41103322;