1-18365223-G-A

Position:

• chr1-18365223-G-A

Variant summary

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

The NM_032880.5(IGSF21):​c.541G>A​(p.Val181Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: IGSF21 NM_032880.5 missense, splice_region
• Scores: Splicing: ADA: 0.9930
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.11

Genes affected

IGSF21 (HGNC:28246): (immunoglobin superfamily member 21) This gene encodes a protein which has two immunoglobulin (Ig) domains and is a member of the immunoglobulin superfamily. Proteins in this superfamily are usually found on or in cell membranes and act as receptors in immune response pathways. [provided by RefSeq, Sep 2011]

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
IGSF21	NM_032880.5	c.541G>A	p.Val181Ile	missense_variant, splice_region_variant	6/10	ENST00000251296.4	NP_116269.3
IGSF21	XM_017002604.3	c.523G>A	p.Val175Ile	missense_variant, splice_region_variant	6/10		XP_016858093.1
IGSF21	XM_017002605.1	c.310G>A	p.Val104Ile	missense_variant, splice_region_variant	5/9		XP_016858094.1
IGSF21	XM_011542319.4	c.425-11087G>A		intron_variant			XP_011540621.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGSF21	ENST00000251296.4	c.541G>A	p.Val181Ile	missense_variant, splice_region_variant	6/10	1	NM_032880.5	ENSP00000251296.1
IGSF21	ENST00000412684.3	n.398G>A		splice_region_variant, non_coding_transcript_exon_variant	5/6	5
IGSF21	ENST00000497331.2	n.865G>A		splice_region_variant, non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Apr 18, 2023

The c.541G>A (p.V181I) alteration is located in exon 6 (coding exon 6) of the IGSF21 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the valine (V) at amino acid position 181 to be replaced by an isoleucine (I). 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	Benign	0.15
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.16
Sift	Benign	0.29	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.73
MutPred		0.29		Loss of ubiquitination at K184 (P = 0.093);
MVP		0.54
MPC		0.79
ClinPred		0.92	D
GERP RS		4.8
Varity_R		0.21
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.030		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: chr1-18691717;