chr15-71215207-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_024817.3(THSD4):ā€‹c.272A>Gā€‹(p.Gln91Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,361,898 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000053 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000025 ( 0 hom. )

Consequence

THSD4
NM_024817.3 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.247
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.04623565).
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000528 (8/151418) while in subpopulation AMR AF= 0.000461 (7/15168). AF 95% confidence interval is 0.000216. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
THSD4NM_024817.3 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/18 ENST00000261862.8
THSD4NM_001394532.1 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/18
THSD4XM_047433080.1 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/18

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
THSD4ENST00000261862.8 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/185 NM_024817.3 P1Q6ZMP0-1
THSD4ENST00000355327.7 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/185 P1Q6ZMP0-1
THSD4ENST00000620694.1 linkuse as main transcriptc.272A>G p.Gln91Arg missense_variant 4/43

Frequencies

GnomAD3 genomes
AF:
0.0000528
AC:
8
AN:
151418
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000461
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000148
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000248
AC:
3
AN:
1210480
Hom.:
0
Cov.:
31
AF XY:
0.00000169
AC XY:
1
AN XY:
592058
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000204
GnomAD4 genome
AF:
0.0000528
AC:
8
AN:
151418
Hom.:
0
Cov.:
33
AF XY:
0.0000406
AC XY:
3
AN XY:
73920
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000461
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000148
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000793

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 16, 2024The c.272A>G (p.Q91R) alteration is located in exon 3 (coding exon 3) of the THSD4 gene. This alteration results from a A to G substitution at nucleotide position 272, causing the glutamine (Q) at amino acid position 91 to be replaced by an arginine (R). 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
0.064
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
0.54
DANN
Benign
0.15
DEOGEN2
Benign
0.012
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.048
N
LIST_S2
Benign
0.19
T;T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.046
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.0
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.74
T
PROVEAN
Benign
0.25
N;.
REVEL
Benign
0.017
Sift
Benign
0.85
T;.
Sift4G
Benign
0.53
T;T
Polyphen
0.020
B;.
Vest4
0.10
MutPred
0.38
Gain of methylation at Q91 (P = 0.0267);Gain of methylation at Q91 (P = 0.0267);
MVP
0.030
MPC
0.12
ClinPred
0.016
T
GERP RS
-1.2
Varity_R
0.024
gMVP
0.23

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1490765758; hg19: chr15-71507546; API