chr15-65384959-T-C

Variant names:

• chr15-65384959-T-C
• rs757195707
• NM_020962.3:c.3337A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020962.3(IGDCC4):​c.3337A>G​(p.Ile1113Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,166 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: IGDCC4 NM_020962.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08685866).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGDCC4	NM_020962.3	c.3337A>G	p.Ile1113Val	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.3337A>G	p.Ile1113Val	missense_variant	Exon 19 of 20	1	NM_020962.3	ENSP00000319623.3
IGDCC4	ENST00000559327.1	n.2606A>G		non_coding_transcript_exon_variant	Exon 13 of 14	1
IGDCC4	ENST00000558048.5	n.469A>G		non_coding_transcript_exon_variant	Exon 2 of 3	2
IGDCC4	ENST00000561309.1	n.358A>G		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151664 Hom.: 0 Cov.: 32

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: 1 AN: 245290 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: 0.00000549 AC: 8 AN: 1458502 Hom.: 0 Cov.: 31 AF XY: 0.00000827 AC XY: 6 AN XY: 725638

African (AFR) AF: 0.00 AC: 0 AN: 32998

American (AMR) AF: 0.00 AC: 0 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.0000697 AC: 6 AN: 86062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110602

Other (OTH) AF: 0.00 AC: 0 AN: 60218

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151664 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74114

African (AFR) AF: 0.00 AC: 0 AN: 40952

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000371 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3337A>G (p.I1113V) alteration is located in exon 19 (coding exon 19) of the IGDCC4 gene. This alteration results from a A to G substitution at nucleotide position 3337, causing the isoleucine (I) at amino acid position 1113 to be replaced by a valine (V). 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	-0.33	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.73
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.032
Sift	Benign	0.29	T
Sift4G	Benign	0.88	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.25		Gain of sheet (P = 0.0344);
MVP		0.36
MPC		0.25
ClinPred		0.065	T
GERP RS		2.6
Varity_R		0.054
gMVP		0.10
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757195707; hg19: chr15-65677297; COSMIC: COSV108883488; COSMIC: COSV108883488;