X-70146758-T-A

Variant names:

• chrX-70146758-T-A
• rs61755732
• NM_001551.3:c.608T>A

Variant summary

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

The NM_001551.3(IGBP1):​c.608T>A​(p.Ile203Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,070,186 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 12/21 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. I203T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: IGBP1 NM_001551.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.49
• Publications: 0 publications found

Genes affected

IGBP1 (HGNC:5461): (immunoglobulin binding protein 1) The proliferation and differentiation of B cells is dependent upon a B-cell antigen receptor (BCR) complex. Binding of antigens to specific B-cell receptors results in a tyrosine phosphorylation reaction through the BCR complex and leads to multiple signal transduction pathways. [provided by RefSeq, Jul 2008]

IGBP1 Gene-Disease associations (from GenCC):

• corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome

  Inheritance: XL, Unknown, AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001551.3. 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
	IGBP1	NM_001551.3	MANE Select	c.608T>A	p.Ile203Asn	missense	Exon 4 of 7	NP_001542.1	P78318
	IGBP1	NM_001370192.1		c.608T>A	p.Ile203Asn	missense	Exon 4 of 7	NP_001357121.1	P78318
	IGBP1	NM_001370193.1		c.608T>A	p.Ile203Asn	missense	Exon 4 of 7	NP_001357122.1	P78318

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGBP1	ENST00000356413.5	TSL:1 MANE Select	c.608T>A	p.Ile203Asn	missense	Exon 4 of 7	ENSP00000348784.4	P78318
	IGBP1	ENST00000342206.10	TSL:1	c.608T>A	p.Ile203Asn	missense	Exon 3 of 6	ENSP00000363661.5	P78318
	IGBP1	ENST00000937166.1		c.608T>A	p.Ile203Asn	missense	Exon 4 of 7	ENSP00000607225.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000280 AC: 3 AN: 1070186 Hom.: 0 Cov.: 29 AF XY: 0.00000291 AC XY: 1 AN XY: 343554

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

African (AFR) AF: 0.0000400 AC: 1 AN: 24990

American (AMR) AF: 0.00 AC: 0 AN: 35108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19147

East Asian (EAS) AF: 0.00 AC: 0 AN: 29967

South Asian (SAS) AF: 0.0000188 AC: 1 AN: 53214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4073

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818148

Other (OTH) AF: 0.00 AC: 0 AN: 45090

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.020	T
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.046	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.49	T
Polyphen		0.79	P
Vest4		0.54
MutPred		0.40		Loss of stability (P = 0.0579)
MVP		0.39
MPC		1.3
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.27
gMVP		0.56
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs61755732; hg19: chrX-69366608;