15-65329550-C-T

Variant names:

• chr15-65329550-C-T
• rs1170692199
• NM_004884.4:c.2045G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004884.4(IGDCC3):​c.2045G>A​(p.Gly682Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,146 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: IGDCC3 NM_004884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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]

ACMG classification

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=0.257863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC3	NM_004884.4	c.2045G>A	p.Gly682Asp	missense_variant	Exon 13 of 14	ENST00000327987.9	NP_004875.2
IGDCC3	XM_011522241.3	c.2045G>A	p.Gly682Asp	missense_variant	Exon 13 of 14		XP_011520543.3
IGDCC3	XM_011522243.1	c.1676G>A	p.Gly559Asp	missense_variant	Exon 12 of 13		XP_011520545.1
IGDCC3	XM_011522244.2	c.1634G>A	p.Gly545Asp	missense_variant	Exon 12 of 13		XP_011520546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGDCC3	ENST00000327987.9	c.2045G>A	p.Gly682Asp	missense_variant	Exon 13 of 14	1	NM_004884.4	ENSP00000332773.4
IGDCC3	ENST00000558354.5	c.*29G>A		downstream_gene_variant		5		ENSP00000454105.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458146 Hom.: 0 Cov.: 35 AF XY: 0.00000414 AC XY: 3 AN XY: 725484

Gnomad4 AFR exome AF: 0.0000904

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2045G>A (p.G682D) alteration is located in exon 13 (coding exon 13) of the IGDCC3 gene. This alteration results from a G to A substitution at nucleotide position 2045, causing the glycine (G) at amino acid position 682 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.066
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.060
Sift	Benign	0.032	D
Sift4G	Benign	0.090	T
Polyphen		0.73	P
Vest4		0.47
MutPred		0.33		Gain of sheet (P = 0.0344);
MVP		0.77
MPC		0.21
ClinPred		0.81	D
GERP RS		3.4
Varity_R		0.11
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1170692199; hg19: chr15-65621888;