19-40606426-C-T

Variant names:

• chr19-40606426-C-T
• rs374427407
• NM_001042545.2:c.891C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001042545.2(LTBP4):​c.891C>T​(p.Gly297Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,594,500 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 (★★). Synonymous variant affecting the same amino acid position (i.e. G297G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (25 hom.)
• Consequence: LTBP4 NM_001042545.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -4.80
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 19-40606426-C-T is Benign according to our data. Variant chr19-40606426-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 504729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.8 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0036 (548/152322) while in subpopulation NFE AF = 0.0052 (354/68022). AF 95% confidence interval is 0.00476. There are 2 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.891C>T	p.Gly297Gly	synonymous	Exon 6 of 30	NP_001036010.1	Q8N2S1-2
	LTBP4	NM_001042544.1		c.1092C>T	p.Gly364Gly	synonymous	Exon 9 of 33	NP_001036009.1	Q8N2S1-1
	LTBP4	NM_003573.2		c.981C>T	p.Gly327Gly	synonymous	Exon 9 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.891C>T	p.Gly297Gly	synonymous	Exon 6 of 30	ENSP00000380031.5	Q8N2S1-2
	LTBP4	ENST00000308370.11	TSL:1	c.1092C>T	p.Gly364Gly	synonymous	Exon 9 of 33	ENSP00000311905.8	Q8N2S1-1
	LTBP4	ENST00000204005.13	TSL:1	c.981C>T	p.Gly327Gly	synonymous	Exon 9 of 33	ENSP00000204005.10	A0A0C4DH07

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 549 AN: 152206 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00810

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00394 AC: 864 AN: 219296 AF XY: 0.00420

Gnomad AFR exome AF: 0.000253

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.0000617

Gnomad FIN exome AF: 0.00825

Gnomad NFE exome AF: 0.00519

Gnomad OTH exome AF: 0.00291

GnomAD4 exome AF: 0.00396 AC: 5717 AN: 1442178 Hom.: 25 Cov.: 40 AF XY: 0.00399 AC XY: 2852 AN XY: 714816

African (AFR) AF: 0.000514 AC: 17 AN: 33094

American (AMR) AF: 0.00157 AC: 67 AN: 42786

Ashkenazi Jewish (ASJ) AF: 0.00194 AC: 50 AN: 25770

East Asian (EAS) AF: 0.0000516 AC: 2 AN: 38764

South Asian (SAS) AF: 0.00365 AC: 306 AN: 83738

European-Finnish (FIN) AF: 0.00720 AC: 366 AN: 50824

Middle Eastern (MID) AF: 0.00383 AC: 22 AN: 5738

European-Non Finnish (NFE) AF: 0.00426 AC: 4695 AN: 1101898

Other (OTH) AF: 0.00322 AC: 192 AN: 59566

GnomAD4 genome AF: 0.00360 AC: 548 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00379 AC XY: 282 AN XY: 74476

African (AFR) AF: 0.000481 AC: 20 AN: 41580

American (AMR) AF: 0.00288 AC: 44 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4826

European-Finnish (FIN) AF: 0.00810 AC: 86 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00520 AC: 354 AN: 68022

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00456 Hom.: 1

Bravo AF: 0.00254

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies (1)
-	-	1	LTBP4-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.8
DANN	Benign	0.96
PhyloP100		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs374427407; hg19: chr19-41112332; COSMIC: COSV99180287; COSMIC: COSV99180287;