1-159943052-T-G

Position:

• chr1-159943052-T-G

Variant summary

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

The NM_001135050.2(IGSF9):​c.158A>C​(p.His53Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H53R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGSF9 NM_001135050.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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 (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/exons	MANE	Protein	UniProt
IGSF9	NM_001135050.2	c.158A>C	p.His53Pro	missense_variant	3/21	ENST00000368094.6	NP_001128522.1
IGSF9	NM_020789.4	c.158A>C	p.His53Pro	missense_variant	3/21		NP_065840.2
LOC124904438	XR_007066684.1	n.78+1606T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF9	ENST00000368094.6	c.158A>C	p.His53Pro	missense_variant	3/21	1	NM_001135050.2	ENSP00000357073.1
IGSF9	ENST00000361509.7	c.158A>C	p.His53Pro	missense_variant	3/21	1		ENSP00000355049.3
IGSF9	ENST00000476102.1	n.353A>C		non_coding_transcript_exon_variant	3/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jan 26, 2022

The c.158A>C (p.H53P) alteration is located in exon 3 (coding exon 2) of the IGSF9 gene. This alteration results from a A to C substitution at nucleotide position 158, causing the histidine (H) at amino acid position 53 to be replaced by a proline (P). 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	0.64
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	.;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.18	N;N;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.9	D;D;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.68
MutPred		0.65		Gain of glycosylation at H53 (P = 0.0961);Gain of glycosylation at H53 (P = 0.0961);Gain of glycosylation at H53 (P = 0.0961);
MVP		0.29
MPC		0.66
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.85

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: chr1-159912842;