15-65385012-G-C

Variant names:

• chr15-65385012-G-C
• rs779710828
• NM_020962.3:c.3284C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020962.3(IGDCC4):​c.3284C>G​(p.Pro1095Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1095L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IGDCC4 NM_020962.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.93
• Publications: 0 publications found

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]

ACMG classification

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=0.38946396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC4	NM_020962.3	c.3284C>G	p.Pro1095Arg	missense_variant	Exon 19 of 20	ENST00000352385.3	NP_066013.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGDCC4	ENST00000352385.3	c.3284C>G	p.Pro1095Arg	missense_variant	Exon 19 of 20	1	NM_020962.3	ENSP00000319623.3
IGDCC4	ENST00000559327.1	n.2553C>G		non_coding_transcript_exon_variant	Exon 13 of 14	1
IGDCC4	ENST00000558048.5	n.416C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
IGDCC4	ENST00000561309.1	n.305C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457604 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725232

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33078

American (AMR) AF: 0.00 AC: 0 AN: 43904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25984

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110534

Other (OTH) AF: 0.00 AC: 0 AN: 60222

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.025	T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.22
Sift	Uncertain	0.019	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.46
MutPred		0.49		Loss of glycosylation at P1095 (P = 0.0119);
MVP		0.56
MPC		0.96
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.091
gMVP		0.38

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

Other links and lift over

dbSNP: rs779710828; hg19: chr15-65677350;