chr11-18704503-C-G

Variant names:

• chr11-18704503-C-G
• rs933925607
• NM_173588.4:c.3946G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173588.4(IGSF22):​c.3946G>C​(p.Glu1316Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,398,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign 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. E1316K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IGSF22 NM_173588.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 0 publications found

Genes affected

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

TMEM86A (HGNC:26890): (transmembrane protein 86A) Predicted to enable alkenylglycerophosphocholine hydrolase activity and alkenylglycerophosphoethanolamine hydrolase activity. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.13624853).

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.3946G>C	p.Glu1316Gln	missense	Exon 23 of 23	NP_775859.4	Q8N9C0-2
	TMEM86A	NM_153347.3	MANE Select	c.*2494C>G		3_prime_UTR	Exon 3 of 3	NP_699178.1	Q8N2M4
	IGSF22	NR_160413.1		n.3702G>C		non_coding_transcript_exon	Exon 21 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGSF22	ENST00000513874.6	TSL:5 MANE Select	c.3946G>C	p.Glu1316Gln	missense	Exon 23 of 23	ENSP00000421191.1	Q8N9C0-2
	TMEM86A	ENST00000280734.3	TSL:1 MANE Select	c.*2494C>G		3_prime_UTR	Exon 3 of 3	ENSP00000280734.2	Q8N2M4
	IGSF22	ENST00000319338.6	TSL:2	n.*842G>C		non_coding_transcript_exon	Exon 21 of 21	ENSP00000322422.6	Q8N9C0-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1398712 Hom.: 0 Cov.: 29 AF XY: 0.00000145 AC XY: 1 AN XY: 689928

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078608

Other (OTH) AF: 0.00 AC: 0 AN: 57978

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.99
Eigen	Benign	-0.082
Eigen_PC	Benign	-0.098
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.062
Sift	Benign	0.16	T
Sift4G	Benign	0.14	T
Vest4		0.15
MutPred		0.26		Gain of MoRF binding (P = 0.02)
MVP		0.37
MPC		0.40
ClinPred		0.43	T
GERP RS		4.4
gMVP		0.31
Mutation Taster		=97/3	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: rs933925607; hg19: chr11-18726050;