19-40597342-G-A

Position:

• chr19-40597342-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000308370.11(LTBP4):​c.108G>A​(p.Gln36=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,523,558 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00070 (18 hom.)
• Consequence: LTBP4 ENST00000308370.11 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.685

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 19-40597342-G-A is Benign according to our data. Variant chr19-40597342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 666629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.685 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00558 (849/152244) while in subpopulation AFR AF= 0.0194 (804/41550). AF 95% confidence interval is 0.0182. There are 9 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBP4	NM_001042544.1	c.108G>A	p.Gln36=	synonymous_variant	1/33
LTBP4	NM_003573.2	c.17-1855G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBP4	ENST00000308370.11	c.108G>A	p.Gln36=	synonymous_variant	1/33	1		A2
LTBP4	ENST00000204005.13	c.17-1855G>A		intron_variant		1		A2
LTBP4	ENST00000599016.5	c.17-1855G>A		intron_variant, NMD_transcript_variant		3
LTBP4	ENST00000600026.5	c.17-1855G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152126 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.000162

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.000867 AC: 104 AN: 119928 Hom.: 3 AF XY: 0.000697 AC XY: 46 AN XY: 66044

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.000742

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000954

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000195

Gnomad OTH exome AF: 0.000831

GnomAD4 exome AF: 0.000696 AC: 955 AN: 1371314 Hom.: 18 Cov.: 33 AF XY: 0.000672 AC XY: 455 AN XY: 676724

Gnomad4 AFR exome AF: 0.0225

Gnomad4 AMR exome AF: 0.00106

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000771

Gnomad4 FIN exome AF: 0.0000289

Gnomad4 NFE exome AF: 0.0000895

Gnomad4 OTH exome AF: 0.00211

GnomAD4 genome AF: 0.00558 AC: 849 AN: 152244 Hom.: 9 Cov.: 30 AF XY: 0.00544 AC XY: 405 AN XY: 74434

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00295 Hom.: 0

Bravo AF: 0.00627

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 31, 2018

The p.Gln36Gln variant in LTBP4 is classified as benign because it has been iden tified in 1.8% (223/12680) of African chromosomes including 4 homozygotes by gno mAD (http://gnomad.broadinstitute.org). ACMG/AMP criteria applied: BA1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

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

Publications

LitVar

Other links and lift over

dbSNP: rs184935788; hg19: chr19-41103248;