Genetic Variant IGDCC4:p.Pro1232Ser (chr15-65384068-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020962.3(IGDCC4):c.3694C>T(p.Pro1232Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 6.8e-7 ( 0 hom. )

Consequence

IGDCC4
NM_020962.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17971763).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC4	NM_020962.3 link	c.3694C>T	p.Pro1232Ser	missense_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.3694C>T	p.Pro1232Ser	missense_variant	Exon 20 of 20	1	NM_020962.3	ENSP00000319623.3	Q8TDY8-1
IGDCC4	ENST00000559327.1 link	n.2963C>T		non_coding_transcript_exon_variant	Exon 14 of 14	1
IGDCC4	ENST00000558048.5 link	n.826C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461082

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726728

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86162

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53360

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111530

Other (OTH)

AF:

0.00

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3694C>T (p.P1232S) alteration is located in exon 20 (coding exon 20) of the IGDCC4 gene. This alteration results from a C to T substitution at nucleotide position 3694, causing the proline (P) at amino acid position 1232 to be replaced by a serine (S). 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

0.089

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0095

Eigen

Benign

0.095

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

M_CAP

Benign

0.077

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

PhyloP100

2.1

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.74

REVEL

Benign

0.060

Sift

Benign

0.36

Sift4G

Benign

0.54

Polyphen

0.86

Vest4

0.10

MutPred

0.11

Loss of catalytic residue at P1232 (P = 0.001);

MVP

0.50

MPC

0.30

ClinPred

0.39

GERP RS

4.7

Varity_R

0.077

gMVP

0.25

Mutation Taster

=88/12

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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chr15-65384068-G-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