11-18706968-C-A

Variant names:

• chr11-18706968-C-A
• rs1564866759
• NM_173588.4:c.3526G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_173588.4(IGSF22):​c.3526G>T​(p.Gly1176Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000166 in 1,389,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1176S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: IGSF22 NM_173588.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.35
• Publications: 0 publications found

Genes affected

IGSF22 (HGNC:26750): (immunoglobulin superfamily member 22)

IGSF22-AS1 (HGNC:55511): (IGSF22 antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173588.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF22	NM_173588.4	MANE Select	c.3526G>T	p.Gly1176Cys	missense	Exon 21 of 23	NP_775859.4	Q8N9C0-2
	IGSF22	NR_160413.1		n.3282G>T		non_coding_transcript_exon	Exon 19 of 21
	IGSF22-AS1	NR_186353.1		n.488C>A		non_coding_transcript_exon	Exon 1 of 3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF22	ENST00000513874.6	TSL:5 MANE Select	c.3526G>T	p.Gly1176Cys	missense	Exon 21 of 23	ENSP00000421191.1	Q8N9C0-2
	IGSF22	ENST00000319338.6	TSL:2	n.*422G>T		non_coding_transcript_exon	Exon 19 of 21	ENSP00000322422.6	Q8N9C0-1
	IGSF22-AS1	ENST00000527285.1	TSL:3	n.432C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000687 AC: 1 AN: 145542 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000166 AC: 23 AN: 1389240 Hom.: 0 Cov.: 29 AF XY: 0.0000175 AC XY: 12 AN XY: 684006

African (AFR) AF: 0.00 AC: 0 AN: 31522

American (AMR) AF: 0.00 AC: 0 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24350

East Asian (EAS) AF: 0.00 AC: 0 AN: 35644

South Asian (SAS) AF: 0.00 AC: 0 AN: 77314

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.0000205 AC: 22 AN: 1073184

Other (OTH) AF: 0.0000174 AC: 1 AN: 57592

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.62	T
PhyloP100		2.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Benign	0.21
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.67
MutPred		0.90		Loss of disorder (P = 0.0262)
MVP		0.59
MPC		0.86
ClinPred		0.98	D
GERP RS		1.8
gMVP		0.89
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1564866759; hg19: chr11-18728515;