rs786205669

Variant names:

• chr13-52397636-C-T
• rs786205669
• NM_018676.4:c.617G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PP3_Strong PP5_Moderate

The NM_018676.4(THSD1):​c.617G>A​(p.Cys206Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: THSD1 NM_018676.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 6.70
• Publications: 3 publications found

Genes affected

THSD1 (HGNC:17754): (thrombospondin type 1 domain containing 1) The protein encoded by this gene contains a type 1 thrombospondin domain, which is found in a number of proteins involved in the complement pathway, as well as in extracellular matrix proteins. Alternatively spliced transcript variants encoding different isoforms have been observed for this gene. [provided by RefSeq, Jan 2009]

THSD1 Gene-Disease associations (from GenCC):

• non-immune hydrops fetalis

  Inheritance: AR Classification: DEFINITIVE Submitted by: King Faisal Specialist Hospital and Research Center
• aneurysm, intracranial berry, 12

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• lymphatic malformation 13

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• intracranial berry aneurysm

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 13-52397636-C-T is Pathogenic according to our data. Variant chr13-52397636-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190456.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
THSD1	NM_018676.4	c.617G>A	p.Cys206Tyr	missense_variant	Exon 3 of 5	ENST00000258613.5	NP_061146.1
THSD1	NM_199263.3	c.617G>A	p.Cys206Tyr	missense_variant	Exon 3 of 4		NP_954872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
THSD1	ENST00000258613.5	c.617G>A	p.Cys206Tyr	missense_variant	Exon 3 of 5	1	NM_018676.4	ENSP00000258613.4
THSD1	ENST00000349258.8	c.617G>A	p.Cys206Tyr	missense_variant	Exon 3 of 4	1		ENSP00000340650.4
THSD1	ENST00000648254.1	c.617G>A	p.Cys206Tyr	missense_variant	Exon 3 of 4			ENSP00000497520.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Lymphatic malformation 13 Pathogenic:2

Jun 03, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 17, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Non-immune hydrops fetalis Pathogenic:1

Oct 30, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	.;T;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.040	T
MutationAssessor	Uncertain	2.7	M;M;M
PhyloP100		6.7
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-11	D;D;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.78		Gain of phosphorylation at C206 (P = 0.0768);Gain of phosphorylation at C206 (P = 0.0768);Gain of phosphorylation at C206 (P = 0.0768);
MVP		0.85
MPC		1.2
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.91
gMVP		0.96
Mutation Taster		=13/87	disease causing (ClinVar)

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: rs786205669; hg19: chr13-52971771;