15-71215226-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_024817.3(THSD4):c.291G>A(p.Ala97=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,410,700 control chromosomes in the GnomAD database, including 9,996 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1295 hom., cov: 33)
  • Exomes 𝑓: 0.11 (8701 hom.)
• Consequence: THSD4 NM_024817.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.552

Genes affected

THSD4 (HGNC:25835): (thrombospondin type 1 domain containing 4) Predicted to enable hydrolase activity. Predicted to be an extracellular matrix structural constituent. Predicted to act upstream of or within elastic fiber assembly. Located in collagen-containing extracellular matrix and extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 15-71215226-G-A is Benign according to our data. Variant chr15-71215226-G-A is described in ClinVar as [Benign]. Clinvar id is 2691047.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-71215226-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.552 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THSD4	NM_024817.3	c.291G>A	p.Ala97=	synonymous_variant	4/18	ENST00000261862.8
THSD4	NM_001394532.1	c.291G>A	p.Ala97=	synonymous_variant	4/18
THSD4	XM_047433080.1	c.291G>A	p.Ala97=	synonymous_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8	c.291G>A	p.Ala97=	synonymous_variant	4/18	5	NM_024817.3	P1
THSD4	ENST00000355327.7	c.291G>A	p.Ala97=	synonymous_variant	4/18	5		P1
THSD4	ENST00000620694.1	c.291G>A	p.Ala97=	synonymous_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18638 AN: 151550 Hom.: 1293 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.0881

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.00444

Gnomad SAS AF: 0.107

Gnomad FIN AF: 0.0839

Gnomad MID AF: 0.159

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.118 AC: 5085 AN: 42950 Hom.: 352 AF XY: 0.123 AC XY: 3140 AN XY: 25534

Gnomad AFR exome AF: 0.228

Gnomad AMR exome AF: 0.0749

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.00361

Gnomad SAS exome AF: 0.147

Gnomad FIN exome AF: 0.0980

Gnomad NFE exome AF: 0.124

Gnomad OTH exome AF: 0.125

GnomAD4 exome AF: 0.114 AC: 143265 AN: 1259044 Hom.: 8701 Cov.: 32 AF XY: 0.114 AC XY: 70645 AN XY: 618206

Gnomad4 AFR exome AF: 0.200

Gnomad4 AMR exome AF: 0.0794

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.00145

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.0936

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.123 AC: 18658 AN: 151656 Hom.: 1295 Cov.: 33 AF XY: 0.119 AC XY: 8822 AN XY: 74128

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.0880

Gnomad4 ASJ AF: 0.114

Gnomad4 EAS AF: 0.00445

Gnomad4 SAS AF: 0.107

Gnomad4 FIN AF: 0.0839

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.125

Alfa AF: 0.120 Hom.: 161

Bravo AF: 0.127

Asia WGS AF: 0.0700 AC: 242 AN: 3436

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
Cadd	Benign	7.9
Dann	Benign	0.91

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: rs78239928; hg19: chr15-71507565; COSMIC: COSV55961210;