Genetic Variant NM_020962.3:c.3344G>A (chr15-65384418-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020962.3(IGDCC4):c.3344G>A(p.Gly1115Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000368 in 1,357,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

IGDCC4
NM_020962.3 missense, splice_region

Scores

Splicing: ADA: 0.3648

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.06

Publications

0 publications found

Variant links:

Genes affected

IGDCC4 (HGNC:13770): (immunoglobulin superfamily DCC subclass member 4) Predicted to be located in plasma membrane. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

IGDCC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31250316).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC4	NM_020962.3 link	c.3344G>A	p.Gly1115Asp	missense_variant, splice_region_variant	Exon 20 of 20	ENST00000352385.3	NP_066013.1	Q8TDY8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IGDCC4	ENST00000352385.3 link	c.3344G>A	p.Gly1115Asp	missense_variant, splice_region_variant	Exon 20 of 20	1	NM_020962.3	ENSP00000319623.3	Q8TDY8-1
IGDCC4	ENST00000559327.1 link	n.2613G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 14 of 14	1
IGDCC4	ENST00000558048.5 link	n.476G>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

171832

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000368

AC:

AN:

1357006

Hom.:

Cov.:

AF XY:

0.00000451

AC XY:

AN XY:

665146

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30354

American (AMR)

AF:

0.00

AC:

AN:

30198

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20152

East Asian (EAS)

AF:

0.00

AC:

AN:

38780

South Asian (SAS)

AF:

0.00

AC:

AN:

70908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00000469

AC:

AN:

1065898

Other (OTH)

AF:

0.00

AC:

AN:

56238

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3344G>A (p.G1115D) alteration is located in exon 20 (coding exon 20) of the IGDCC4 gene. This alteration results from a G to A substitution at nucleotide position 3344, causing the glycine (G) at amino acid position 1115 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

0.23

BayesDel_addAF

Uncertain

0.039

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0099

Eigen

Benign

-0.16

Eigen_PC

Benign

0.039

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.70

M_CAP

Benign

0.011

MetaRNN

Benign

0.31

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

3.1

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.43

REVEL

Benign

0.12

Sift

Benign

0.11

Sift4G

Benign

0.75

Polyphen

0.11

Vest4

0.62

MutPred

0.30

Loss of sheet (P = 0.0104);

MVP

0.44

MPC

0.45

ClinPred

0.52

GERP RS

5.1

Varity_R

0.13

gMVP

0.16

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.36

dbscSNV1_RF

Benign

0.32

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

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NM_020962.3:c.3344G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over