15-71215215-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024817.3(THSD4):c.280G>A(p.Gly94Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000646 in 1,377,854 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G94G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (1 hom.)
• Consequence: THSD4 NM_024817.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.878

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011858612).
• BP6: Variant 15-71215215-G-A is Benign according to our data. Variant chr15-71215215-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2385042.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000461 (7/151692) while in subpopulation SAS AF= 0.00145 (7/4830). AF 95% confidence interval is 0.000679. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THSD4	NM_024817.3	c.280G>A	p.Gly94Ser	missense_variant	4/18	ENST00000261862.8
THSD4	NM_001394532.1	c.280G>A	p.Gly94Ser	missense_variant	4/18
THSD4	XM_047433080.1	c.280G>A	p.Gly94Ser	missense_variant	4/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8	c.280G>A	p.Gly94Ser	missense_variant	4/18	5	NM_024817.3	P1
THSD4	ENST00000355327.7	c.280G>A	p.Gly94Ser	missense_variant	4/18	5		P1
THSD4	ENST00000620694.1	c.280G>A	p.Gly94Ser	missense_variant	4/4	3

Frequencies

GnomAD3 genomes AF: 0.0000462 AC: 7 AN: 151584 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000219 AC: 7 AN: 31982 Hom.: 0 AF XY: 0.000258 AC XY: 5 AN XY: 19390

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000841

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000782

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000669 AC: 82 AN: 1226162 Hom.: 1 Cov.: 31 AF XY: 0.0000833 AC XY: 50 AN XY: 600528

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000498

Gnomad4 OTH exome AF: 0.000100

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151692 Hom.: 0 Cov.: 33 AF XY: 0.0000540 AC XY: 4 AN XY: 74138

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000822 AC: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	0.72
Dann	Benign	0.80
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.14	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.050	N;.
REVEL	Benign	0.0080
Sift	Benign	0.78	T;.
Sift4G	Benign	0.88	T;T
Polyphen		0.0010	B;.
Vest4		0.14
MutPred		0.21		Gain of glycosylation at G94 (P = 0.031);Gain of glycosylation at G94 (P = 0.031);
MVP		0.014
MPC		0.11
ClinPred		0.013	T
GERP RS		-3.9
Varity_R		0.041
gMVP		0.25

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: rs746860013; hg19: chr15-71507554;