chr11-18706968-C-T

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_173588.4(IGSF22):​c.3526G>A​(p.Gly1176Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000288 in 1,389,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: IGSF22 NM_173588.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.35

Genes affected

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

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGSF22	NM_173588.4	c.3526G>A	p.Gly1176Ser	missense_variant	Exon 21 of 23	ENST00000513874.6	NP_775859.4
IGSF22	XM_047426830.1	c.1600G>A	p.Gly534Ser	missense_variant	Exon 8 of 10		XP_047282786.1
IGSF22	NR_160413.1	n.3282G>A		non_coding_transcript_exon_variant	Exon 19 of 21
IGSF22-AS1	NR_186353.1	n.488C>T		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGSF22	ENST00000513874.6	c.3526G>A	p.Gly1176Ser	missense_variant	Exon 21 of 23	5	NM_173588.4	ENSP00000421191.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000687 AC: 1 AN: 145542 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 76644

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 SAS 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: 0.00000288 AC: 4 AN: 1389242 Hom.: 0 Cov.: 29 AF XY: 0.00000146 AC XY: 1 AN XY: 684006

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: 0.00000186

Gnomad4 OTH exome AF: 0.0000347

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3526G>A (p.G1176S) alteration is located in exon 21 (coding exon 20) of the IGSF22 gene. This alteration results from a G to A substitution at nucleotide position 3526, causing the glycine (G) at amino acid position 1176 to be replaced by a serine (S). 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
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.067	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.71	T
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.66
MutPred		0.91		Gain of disorder (P = 0.0752);
MVP		0.42
MPC		0.83
ClinPred		0.96	D
GERP RS		1.8
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1564866759; hg19: chr11-18728515;