NM_001135050.2:c.2678G>A

Variant names:

• chr1-159928710-C-T
• rs199795049
• NM_001135050.2:c.2678G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001135050.2(IGSF9):​c.2678G>A​(p.Gly893Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,476,806 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: IGSF9 NM_001135050.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57
• Publications: 2 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044441223).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF9	NM_001135050.2	c.2678G>A	p.Gly893Glu	missense_variant	Exon 19 of 21	ENST00000368094.6	NP_001128522.1
IGSF9	NM_020789.4	c.2630G>A	p.Gly877Glu	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.2678G>A	p.Gly893Glu	missense_variant	Exon 19 of 21	1	NM_001135050.2	ENSP00000357073.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152126 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000499 AC: 48 AN: 96162 AF XY: 0.000373

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000286

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.000181 AC: 240 AN: 1324564 Hom.: 2 Cov.: 35 AF XY: 0.000187 AC XY: 121 AN XY: 645350

African (AFR) AF: 0.0000684 AC: 2 AN: 29236

American (AMR) AF: 0.00211 AC: 49 AN: 23202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19558

East Asian (EAS) AF: 0.00 AC: 0 AN: 35680

South Asian (SAS) AF: 0.00 AC: 0 AN: 66074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46522

Middle Eastern (MID) AF: 0.00396 AC: 21 AN: 5306

European-Non Finnish (NFE) AF: 0.000124 AC: 130 AN: 1044348

Other (OTH) AF: 0.000695 AC: 38 AN: 54638

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74432

African (AFR) AF: 0.0000722 AC: 3 AN: 41538

American (AMR) AF: 0.00124 AC: 19 AN: 15302

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000555

ExAC AF: 0.000351 AC: 40

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2678G>A (p.G893E) 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 2678, causing the glycine (G) at amino acid position 893 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	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.024	.;T
Eigen	Benign	-0.095
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.74	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	.;L
PhyloP100		2.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.26
Sift	Benign	0.22	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.60	.;P
Vest4		0.56
MVP		0.67
MPC		0.40
ClinPred		0.029	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.26
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs199795049; hg19: chr1-159898500; COSMIC: COSV57423675; COSMIC: COSV57423675;