Genetic Variant IGDCC4:p.Thr1102Met (chr15-65384991-G-A) – 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.3305C>T(p.Thr1102Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. T1102A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

IGDCC4
NM_020962.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.88

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:

Genome browser will be placed here

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=0.35244113).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC4	NM_020962.3 link	c.3305C>T	p.Thr1102Met	missense_variant	Exon 19 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.3305C>T	p.Thr1102Met	missense_variant	Exon 19 of 20	1	NM_020962.3	ENSP00000319623.3	Q8TDY8-1
IGDCC4	ENST00000559327.1 link	n.2574C>T		non_coding_transcript_exon_variant	Exon 13 of 14	1
IGDCC4	ENST00000558048.5 link	n.437C>T		non_coding_transcript_exon_variant	Exon 2 of 3	2
IGDCC4	ENST00000561309.1 link	n.326C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000408

AC:

AN:

245096

AF XY:

0.00000750

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1458938

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

725822

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33100

American (AMR)

AF:

0.00

AC:

AN:

44384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26038

East Asian (EAS)

AF:

0.00

AC:

AN:

39452

South Asian (SAS)

AF:

0.00

AC:

AN:

86102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53012

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110822

Other (OTH)

AF:

0.0000166

AC:

AN:

60276

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41082

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2088

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

Alfa

AF:

0.00

Hom.:

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

Feb 12, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3305C>T (p.T1102M) alteration is located in exon 19 (coding exon 19) of the IGDCC4 gene. This alteration results from a C to T substitution at nucleotide position 3305, causing the threonine (T) at amino acid position 1102 to be replaced by a methionine (M). 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

-0.027

BayesDel_noAF

Benign

-0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.84

M_CAP

Benign

0.082

MetaRNN

Benign

0.35

MetaSVM

Benign

-0.62

MutationAssessor

Benign

1.0

PhyloP100

2.9

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.8

REVEL

Benign

0.14

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.024

Polyphen

1.0

Vest4

0.42

MutPred

0.21

Loss of catalytic residue at T1102 (P = 0.0683);

MVP

0.58

MPC

0.95

ClinPred

0.73

GERP RS

5.2

Varity_R

0.071

gMVP

0.35

Mutation Taster

=94/6

polymorphism

(source)

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

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15-65384991-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over