3-118904721-T-G

Position:

• chr3-118904721-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001015887.3(IGSF11):​c.781A>C​(p.Ile261Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: IGSF11 NM_001015887.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

Genes affected

IGSF11 (HGNC:16669): (immunoglobulin superfamily member 11) IGSF11 is an immunoglobulin (Ig) superfamily member that is preferentially expressed in brain and testis. It shares significant homology with coxsackievirus and adenovirus receptor (CXADR; MIM 602621) and endothelial cell-selective adhesion molecule (ESAM).[supplied by OMIM, Apr 2005]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2475515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF11	NM_001015887.3	c.781A>C	p.Ile261Leu	missense_variant	6/7	ENST00000393775.7	NP_001015887.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF11	ENST00000393775.7	c.781A>C	p.Ile261Leu	missense_variant	6/7	1	NM_001015887.3	ENSP00000377370	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461134 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.781A>C (p.I261L) alteration is located in exon 6 (coding exon 6) of the IGSF11 gene. This alteration results from a A to C substitution at nucleotide position 781, causing the isoleucine (I) at amino acid position 261 to be replaced by a leucine (L). 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	0.076
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.0080	.;T;.;.;.
Eigen	Benign	-0.14
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.60	.;T;T;T;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.25	T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	.;L;.;.;.
MutationTaster	Benign	0.96	D;D;D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.80	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.30	T;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T
Polyphen		0.0060	B;B;B;B;B
Vest4		0.46
MutPred		0.56		.;Loss of sheet (P = 0.0084);.;.;.;
MVP		0.69
MPC		0.31
ClinPred		0.52	D
GERP RS		5.3
Varity_R		0.091
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1939363449; hg19: chr3-118623568;