chrX-70146704-A-G

Position:

• chrX-70146704-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001551.3(IGBP1):​c.554A>G​(p.Asp185Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,960 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IGBP1 NM_001551.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.99

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IGBP1	NM_001551.3	c.554A>G	p.Asp185Gly	missense_variant	4/7	ENST00000356413.5	NP_001542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IGBP1	ENST00000356413.5	c.554A>G	p.Asp185Gly	missense_variant	4/7	1	NM_001551.3	ENSP00000348784.4
IGBP1	ENST00000342206.10	c.554A>G	p.Asp185Gly	missense_variant	3/6	1		ENSP00000363661.5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093960 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 359422

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

Bravo AF: 0.00000378

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

Oct 27, 2023

The c.554A>G (p.D185G) alteration is located in exon 4 (coding exon 3) of the IGBP1 gene. This alteration results from a A to G substitution at nucleotide position 554, causing the aspartic acid (D) at amino acid position 185 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.5	H;H
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-6.3	D;D
REVEL	Uncertain	0.55
Sift	Benign	0.031	D;D
Sift4G	Uncertain	0.048	D;D
Polyphen		0.15	B;B
Vest4		0.52
MutPred		0.87		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.97
MPC		1.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs779009512; hg19: chrX-69366554;