15-71154900-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_024817.3(THSD4):c.67G>A(p.Val23Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: THSD4 NM_024817.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

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-AS1 (HGNC:51420): (THSD4 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.043416798).
• BS2: High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
THSD4	NM_024817.3	c.67G>A	p.Val23Ile	missense_variant	3/18	ENST00000261862.8
THSD4	NM_001394532.1	c.67G>A	p.Val23Ile	missense_variant	3/18
THSD4	XM_047433080.1	c.67G>A	p.Val23Ile	missense_variant	3/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
THSD4	ENST00000261862.8	c.67G>A	p.Val23Ile	missense_variant	3/18	5	NM_024817.3	P1
THSD4-AS1	ENST00000561571.5	n.414-7110C>T		intron_variant, non_coding_transcript_variant		5
THSD4	ENST00000355327.7	c.67G>A	p.Val23Ile	missense_variant	3/18	5		P1
THSD4	ENST00000620694.1	c.67G>A	p.Val23Ile	missense_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000481 AC: 12 AN: 249382 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000612

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461844 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727222

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000661 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.67G>A (p.V23I) alteration is located in exon 2 (coding exon 2) of the THSD4 gene. This alteration results from a G to A substitution at nucleotide position 67, causing the valine (V) at amino acid position 23 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.010	N;.
REVEL	Benign	0.019
Sift	Benign	0.15	T;.
Sift4G	Benign	0.11	T;D
Polyphen		0.014	B;.
Vest4		0.14
MVP		0.16
MPC		0.13
ClinPred		0.047	T
GERP RS		1.9
Varity_R		0.025
gMVP		0.12

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: rs374434657; hg19: chr15-71447239;