rs12441227

Variant names:

• chr15-71404547-A-G
• rs12441227
• NM_024817.3:c.1016-7140A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024817.3(THSD4):​c.1016-7140A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 152,192 control chromosomes in the GnomAD database, including 1,952 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.15 (1952 hom., cov: 33)
• Consequence: THSD4 NM_024817.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.217
• Publications: 11 publications found

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]

THSD4 Gene-Disease associations (from GenCC):

• aortic aneurysm, familial thoracic 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Franklin by Genoox

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THSD4	NM_024817.3	c.1016-7140A>G		intron_variant	Intron 6 of 17	ENST00000261862.8	NP_079093.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THSD4	ENST00000261862.8	c.1016-7140A>G		intron_variant	Intron 6 of 17	5	NM_024817.3	ENSP00000261862.8
THSD4	ENST00000355327.7	c.1016-7140A>G		intron_variant	Intron 6 of 17	5		ENSP00000347484.3

Frequencies

GnomAD3 genomes AF: 0.146 AC: 22230 AN: 152074 Hom.: 1943 Cov.: 33

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.133

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.146 AC: 22250 AN: 152192 Hom.: 1952 Cov.: 33 AF XY: 0.150 AC XY: 11139 AN XY: 74398

African (AFR) AF: 0.0561 AC: 2329 AN: 41550

American (AMR) AF: 0.237 AC: 3625 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 444 AN: 3470

East Asian (EAS) AF: 0.108 AC: 560 AN: 5178

South Asian (SAS) AF: 0.188 AC: 907 AN: 4816

European-Finnish (FIN) AF: 0.211 AC: 2237 AN: 10582

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.171 AC: 11612 AN: 67994

Other (OTH) AF: 0.137 AC: 289 AN: 2112

Alfa AF: 0.157 Hom.: 3053

Bravo AF: 0.144

Asia WGS AF: 0.163 AC: 568 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.2
DANN	Benign	0.94
PhyloP100		0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs12441227; hg19: chr15-71696886;