15-65329089-C-A

Variant summary

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

The NM_004884.4(IGDCC3):​c.2265G>T​(p.Gln755His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,611,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

IGDCC3
NM_004884.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.125
Variant links:
Genes affected
IGDCC3 (HGNC:9700): (immunoglobulin superfamily DCC subclass member 3) Predicted to act upstream of or within neuromuscular process controlling balance. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.074469686).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IGDCC3NM_004884.4 linkc.2265G>T p.Gln755His missense_variant Exon 14 of 14 ENST00000327987.9 NP_004875.2 Q8IVU1
IGDCC3XM_011522241.3 linkc.2262G>T p.Gln754His missense_variant Exon 14 of 14 XP_011520543.3
IGDCC3XM_011522243.1 linkc.1896G>T p.Gln632His missense_variant Exon 13 of 13 XP_011520545.1
IGDCC3XM_011522244.2 linkc.1854G>T p.Gln618His missense_variant Exon 13 of 13 XP_011520546.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IGDCC3ENST00000327987.9 linkc.2265G>T p.Gln755His missense_variant Exon 14 of 14 1 NM_004884.4 ENSP00000332773.4 Q8IVU1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000414
AC:
1
AN:
241336
Hom.:
0
AF XY:
0.00000762
AC XY:
1
AN XY:
131214
show subpopulations
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000921
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1459142
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
725758
show subpopulations
Gnomad4 AFR exome
AF:
0.000359
Gnomad4 AMR exome
AF:
0.00
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:
0.000182
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152338
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74496
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000412
AC:
5

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Sep 14, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2265G>T (p.Q755H) alteration is located in exon 14 (coding exon 14) of the IGDCC3 gene. This alteration results from a G to T substitution at nucleotide position 2265, causing the glutamine (Q) at amino acid position 755 to be replaced by a histidine (H). 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
0.24
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
12
DANN
Benign
0.97
DEOGEN2
Benign
0.083
T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.42
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.074
T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
0.90
L
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.24
N
REVEL
Benign
0.045
Sift
Benign
0.034
D
Sift4G
Uncertain
0.048
D
Polyphen
0.41
B
Vest4
0.19
MutPred
0.21
Gain of sheet (P = 0.0221);
MVP
0.73
MPC
0.14
ClinPred
0.085
T
GERP RS
2.2
Varity_R
0.034
gMVP
0.24

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: rs201058521; hg19: chr15-65621427; API