1-159943426-A-C

Variant names:

• chr1-159943426-A-C
• NM_001135050.2:c.29T>G

Variant summary

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

The NM_001135050.2(IGSF9):​c.29T>G​(p.Leu10Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000835 in 1,436,678 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: IGSF9 NM_001135050.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.05

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]

LOC124904438 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF9	NM_001135050.2	c.29T>G	p.Leu10Arg	missense_variant	Exon 2 of 21	ENST00000368094.6	NP_001128522.1
IGSF9	NM_020789.4	c.29T>G	p.Leu10Arg	missense_variant	Exon 2 of 21		NP_065840.2
LOC124904438	XR_007066684.1	n.78+1980A>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF9	ENST00000368094.6	c.29T>G	p.Leu10Arg	missense_variant	Exon 2 of 21	1	NM_001135050.2	ENSP00000357073.1
IGSF9	ENST00000361509.7	c.29T>G	p.Leu10Arg	missense_variant	Exon 2 of 21	1		ENSP00000355049.3
IGSF9	ENST00000476102.1	n.224T>G		non_coding_transcript_exon_variant	Exon 2 of 20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000835 AC: 12 AN: 1436678 Hom.: 0 Cov.: 31 AF XY: 0.00000983 AC XY: 7 AN XY: 712328

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: 0.0000100

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.29T>G (p.L10R) alteration is located in exon 2 (coding exon 1) of the IGSF9 gene. This alteration results from a T to G substitution at nucleotide position 29, causing the leucine (L) at amino acid position 10 to be replaced by an arginine (R). 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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	1.4	L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D;D;.
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.90
MutPred		0.75		Gain of MoRF binding (P = 0.0021);Gain of MoRF binding (P = 0.0021);Gain of MoRF binding (P = 0.0021);
MVP		0.19
MPC		0.46
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.44
gMVP		0.74

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-159913216;