chr19-40592965-C-T

Variant names:

• chr19-40592965-C-T
• rs56013937
• ENST00000600026.5:n.-201C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000600026.5(LTBP4):​n.-201C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.083 in 591,688 control chromosomes in the GnomAD database, including 2,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (571 hom., cov: 32)
  • Exomes 𝑓: 0.082 (1810 hom.)
• Consequence: LTBP4 ENST00000600026.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.785
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 19-40592965-C-T is Benign according to our data. Variant chr19-40592965-C-T is described in ClinVar as Benign. ClinVar VariationId is 678508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000600026.5. 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_003573.2		c.-201C>T		upstream_gene	N/A	NP_003564.2	B3KXY6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP4	ENST00000600026.5	TSL:3	n.-201C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000483230.1	A0A087X0A7
	LTBP4	ENST00000600026.5	TSL:3	n.-201C>T		non_coding_transcript_exon	Exon 1 of 5	ENSP00000483230.1	A0A087X0A7
	LTBP4	ENST00000600026.5	TSL:3	n.-201C>T		5_prime_UTR	Exon 1 of 5	ENSP00000483230.1	A0A087X0A7

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12825 AN: 151892 Hom.: 566 Cov.: 32

Gnomad AFR AF: 0.0988

Gnomad AMI AF: 0.0912

Gnomad AMR AF: 0.0582

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0805

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.0749

GnomAD4 exome AF: 0.0825 AC: 36263 AN: 439678 Hom.: 1810 Cov.: 5 AF XY: 0.0853 AC XY: 19859 AN XY: 232900

African (AFR) AF: 0.0975 AC: 1201 AN: 12320

American (AMR) AF: 0.0430 AC: 944 AN: 21946

Ashkenazi Jewish (ASJ) AF: 0.0825 AC: 1157 AN: 14022

East Asian (EAS) AF: 0.00830 AC: 242 AN: 29166

South Asian (SAS) AF: 0.133 AC: 6186 AN: 46582

European-Finnish (FIN) AF: 0.0838 AC: 2505 AN: 29878

Middle Eastern (MID) AF: 0.0751 AC: 231 AN: 3074

European-Non Finnish (NFE) AF: 0.0843 AC: 21734 AN: 257852

Other (OTH) AF: 0.0831 AC: 2063 AN: 24838

GnomAD4 genome AF: 0.0845 AC: 12843 AN: 152010 Hom.: 571 Cov.: 32 AF XY: 0.0841 AC XY: 6250 AN XY: 74300

African (AFR) AF: 0.0986 AC: 4086 AN: 41446

American (AMR) AF: 0.0581 AC: 887 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.0187 AC: 97 AN: 5174

South Asian (SAS) AF: 0.142 AC: 684 AN: 4824

European-Finnish (FIN) AF: 0.0805 AC: 849 AN: 10546

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0840 AC: 5707 AN: 67974

Other (OTH) AF: 0.0798 AC: 168 AN: 2106

Alfa AF: 0.0868 Hom.: 222

Bravo AF: 0.0815

Asia WGS AF: 0.108 AC: 374 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.7
DANN	Benign	0.64
PhyloP100		-0.79
PromoterAI		0.022	Neutral

Splicing

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

Other links and lift over

dbSNP: rs56013937; hg19: chr19-41098871;