chr1-159928626-C-T

Variant names:

• chr1-159928626-C-T
• rs949883242
• NM_001135050.2:c.2762G>A

Variant summary

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

The NM_001135050.2(IGSF9):​c.2762G>A​(p.Gly921Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,488,996 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: IGSF9 NM_001135050.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.402
• Publications: 0 publications found

Genes affected

IGSF9 (HGNC:18132): (immunoglobulin superfamily member 9) Predicted to enable cell-cell adhesion mediator activity. Predicted to be involved in axon guidance; dendrite self-avoidance; and homophilic cell adhesion via plasma membrane adhesion molecules. Predicted to act upstream of or within dendrite development and regulation of synapse organization. Predicted to be located in dendrite and inhibitory synapse. Predicted to be integral component of membrane. Predicted to be active in axon and plasma 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=0.27788484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF9	NM_001135050.2	c.2762G>A	p.Gly921Glu	missense_variant	Exon 19 of 21	ENST00000368094.6	NP_001128522.1
IGSF9	NM_020789.4	c.2714G>A	p.Gly905Glu	missense_variant	Exon 19 of 21		NP_065840.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF9	ENST00000368094.6	c.2762G>A	p.Gly921Glu	missense_variant	Exon 19 of 21	1	NM_001135050.2	ENSP00000357073.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152026 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.00000853 AC: 1 AN: 117178 AF XY: 0.0000169

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: 0.0000193

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 44 AN: 1336970 Hom.: 0 Cov.: 35 AF XY: 0.0000246 AC XY: 16 AN XY: 651618

African (AFR) AF: 0.00 AC: 0 AN: 30032

American (AMR) AF: 0.00 AC: 0 AN: 24956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19600

East Asian (EAS) AF: 0.00 AC: 0 AN: 37184

South Asian (SAS) AF: 0.00 AC: 0 AN: 66912

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 0.0000400 AC: 42 AN: 1050186

Other (OTH) AF: 0.0000362 AC: 2 AN: 55182

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152026 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74250

African (AFR) AF: 0.0000242 AC: 1 AN: 41390

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67966

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2762G>A (p.G921E) alteration is located in exon 19 (coding exon 18) of the IGSF9 gene. This alteration results from a G to A substitution at nucleotide position 2762, causing the glycine (G) at amino acid position 921 to be replaced by a glutamic acid (E). 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	0.20
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.056	.;T;T
Eigen	Benign	-0.038
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		0.40
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.022	D;D;T
Polyphen		0.99	.;D;.
Vest4		0.50
MutPred		0.26		.;Gain of solvent accessibility (P = 0.0018);.;
MVP		0.39
MPC		0.63
ClinPred		0.78	D
GERP RS		4.6
Varity_R		0.19
gMVP		0.36
Mutation Taster		=55/45	polymorphism

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: rs949883242; hg19: chr1-159898416;