chr11-133919890-C-T

Position:

• chr11-133919890-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277285.4(IGSF9B):​c.3835G>A​(p.Ala1279Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 1,585,618 control chromosomes in the GnomAD database, including 96 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (51 hom.)
• Consequence: IGSF9B NM_001277285.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.52

Genes affected

IGSF9B (HGNC:32326): (immunoglobulin superfamily member 9B) Predicted to enable kinase binding activity. Predicted to be involved in synaptic membrane adhesion. Predicted to act upstream of or within homophilic cell adhesion via plasma membrane adhesion molecules and positive regulation of inhibitory postsynaptic potential. Predicted to be located in dendrite; inhibitory synapse; and neuronal cell body. Predicted to be active in GABA-ergic synapse; neuron projection; and postsynaptic specialization of symmetric synapse. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028766096).
• BP6: Variant 11-133919890-C-T is Benign according to our data. Variant chr11-133919890-C-T is described in ClinVar as [Benign]. Clinvar id is 768498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-133919890-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0148 (2256/152156) while in subpopulation AFR AF= 0.0432 (1791/41496). AF 95% confidence interval is 0.0415. There are 45 homozygotes in gnomad4. There are 1033 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGSF9B	NM_001277285.4	c.3835G>A	p.Ala1279Thr	missense_variant	18/20	ENST00000533871.8	NP_001264214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF9B	ENST00000533871.8	c.3835G>A	p.Ala1279Thr	missense_variant	18/20	5	NM_001277285.4	ENSP00000436552.2
IGSF9B	ENST00000321016.12	c.3835G>A	p.Ala1279Thr	missense_variant	18/19	5		ENSP00000317980.8

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2254 AN: 152036 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.0230

GnomAD3 exomes AF: 0.00550 AC: 1240 AN: 225450 Hom.: 19 AF XY: 0.00440 AC XY: 538 AN XY: 122338

Gnomad AFR exome AF: 0.0448

Gnomad AMR exome AF: 0.00942

Gnomad ASJ exome AF: 0.00524

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00597

GnomAD4 exome AF: 0.00294 AC: 4212 AN: 1433462 Hom.: 51 Cov.: 34 AF XY: 0.00273 AC XY: 1939 AN XY: 710804

Gnomad4 AFR exome AF: 0.0448

Gnomad4 AMR exome AF: 0.00970

Gnomad4 ASJ exome AF: 0.00585

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.00150

Gnomad4 OTH exome AF: 0.00812

GnomAD4 genome AF: 0.0148 AC: 2256 AN: 152156 Hom.: 45 Cov.: 33 AF XY: 0.0139 AC XY: 1033 AN XY: 74390

Gnomad4 AFR AF: 0.0432

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00193

Gnomad4 OTH AF: 0.0227

Alfa AF: 0.00445 Hom.: 9

Bravo AF: 0.0185

ESP6500AA AF: 0.0400 AC: 153

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.00534 AC: 644

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 08, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.010	.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.015
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.89	.;N
REVEL	Benign	0.034
Sift	Benign	0.091	.;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0090	.;B
Vest4		0.18
MVP		0.043
MPC		0.10
ClinPred		0.0064	T
GERP RS		4.8
Varity_R		0.041
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs148045307; hg19: chr11-133789785;