Genetic Variant NM_001135050.2:c.2927C>A (chr1-159928461-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001135050.2(IGSF9):c.2927C>A(p.Ser976Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,784 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: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IGSF9
NM_001135050.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.128

Variant links:

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]

IGSF9 links:

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ACMG classification

Classification was made for transcript

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=0.1017625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF9	NM_001135050.2 link	c.2927C>A	p.Ser976Tyr	missense_variant	Exon 19 of 21	ENST00000368094.6	NP_001128522.1	Q9P2J2-1
IGSF9	NM_020789.4 link	c.2879C>A	p.Ser960Tyr	missense_variant	Exon 19 of 21		NP_065840.2	Q9P2J2-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF9	ENST00000368094.6 link	c.2927C>A	p.Ser976Tyr	missense_variant	Exon 19 of 21	1	NM_001135050.2	ENSP00000357073.1		Q9P2J2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441784

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714590

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33088

American (AMR)

AF:

0.00

AC:

AN:

42078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25338

East Asian (EAS)

AF:

0.00

AC:

AN:

39134

South Asian (SAS)

AF:

0.00

AC:

AN:

84318

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

9.09e-7

AC:

AN:

1100376

Other (OTH)

AF:

0.00

AC:

AN:

59412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2927C>A (p.S976Y) alteration is located in exon 19 (coding exon 18) of the IGSF9 gene. This alteration results from a C to A substitution at nucleotide position 2927, causing the serine (S) at amino acid position 976 to be replaced by a tyrosine (Y). 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

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.036

.;T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.69

T;T;T

M_CAP

Benign

0.059

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

.;L;.

PhyloP100

0.13

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.99

N;N;.

REVEL

Benign

0.079

Sift

Benign

0.073

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.21

.;B;.

Vest4

0.28

MutPred

0.17

.;Loss of glycosylation at S976 (P = 0.0129);.;

MVP

0.12

MPC

0.34

ClinPred

0.081

GERP RS

0.78

Varity_R

0.040

gMVP

0.27

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

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

Publications

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NM_001135050.2:c.2927C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over