1-18365262-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032880.5(IGSF21):​c.580C>A​(p.Pro194Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P194S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IGSF21
NM_032880.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
Variant links:
Genes affected
IGSF21 (HGNC:28246): (immunoglobin superfamily member 21) This gene encodes a protein which has two immunoglobulin (Ig) domains and is a member of the immunoglobulin superfamily. Proteins in this superfamily are usually found on or in cell membranes and act as receptors in immune response pathways. [provided by RefSeq, Sep 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.15861797).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IGSF21NM_032880.5 linkc.580C>A p.Pro194Thr missense_variant Exon 6 of 10 ENST00000251296.4 NP_116269.3 Q96ID5
IGSF21XM_017002604.3 linkc.562C>A p.Pro188Thr missense_variant Exon 6 of 10 XP_016858093.1
IGSF21XM_017002605.1 linkc.349C>A p.Pro117Thr missense_variant Exon 5 of 9 XP_016858094.1
IGSF21XM_011542319.4 linkc.425-11048C>A intron_variant Intron 4 of 7 XP_011540621.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IGSF21ENST00000251296.4 linkc.580C>A p.Pro194Thr missense_variant Exon 6 of 10 1 NM_032880.5 ENSP00000251296.1 Q96ID5
IGSF21ENST00000412684.3 linkn.437C>A non_coding_transcript_exon_variant Exon 5 of 6 5
IGSF21ENST00000497331.2 linkn.904C>A non_coding_transcript_exon_variant Exon 2 of 6 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249446
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134970
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460634
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726506
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000672
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:
0.00
GnomAD4 genome
Cov.:
31
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 05, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.580C>A (p.P194T) alteration is located in exon 6 (coding exon 6) of the IGSF21 gene. This alteration results from a C to A substitution at nucleotide position 580, causing the proline (P) at amino acid position 194 to be replaced by a threonine (T). 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
0.074
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.011
T
Eigen
Benign
-0.51
Eigen_PC
Benign
-0.49
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Benign
0.74
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.77
N
REVEL
Benign
0.022
Sift
Benign
0.12
T
Sift4G
Uncertain
0.041
D
Polyphen
0.34
B
Vest4
0.41
MutPred
0.47
Gain of phosphorylation at P194 (P = 0.0348);
MVP
0.25
MPC
0.40
ClinPred
0.18
T
GERP RS
2.8
Varity_R
0.066
gMVP
0.37

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: rs1254936643; hg19: chr1-18691756; API