NM_020070.4:c.425C>G

Variant names:

• chr22-23573483-G-C
• rs1064422
• NM_020070.4:c.425C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020070.4(IGLL1):​c.425C>G​(p.Pro142Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P142L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.74
• Publications: 0 publications found

Genes affected

IGLL1 (HGNC:5870): (immunoglobulin lambda like polypeptide 1) The preB cell receptor is found on the surface of proB and preB cells, where it is involved in transduction of signals for cellular proliferation, differentiation from the proB cell to the preB cell stage, allelic exclusion at the Ig heavy chain gene locus, and promotion of Ig light chain gene rearrangements. The preB cell receptor is composed of a membrane-bound Ig mu heavy chain in association with a heterodimeric surrogate light chain. This gene encodes one of the surrogate light chain subunits and is a member of the immunoglobulin gene superfamily. This gene does not undergo rearrangement. Mutations in this gene can result in B cell deficiency and agammaglobulinemia, an autosomal recessive disease in which few or no gamma globulins or antibodies are made. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

IGLL1 Gene-Disease associations (from GenCC):

• agammaglobulinemia 2, autosomal recessive

  Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000224277 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020070.4. 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
	IGLL1	NM_020070.4	MANE Select	c.425C>G	p.Pro142Arg	missense	Exon 3 of 3	NP_064455.1	P15814-1
	IGLL1	NM_001369906.1		c.428C>G	p.Pro143Arg	missense	Exon 3 of 3	NP_001356835.1
	IGLL1	NM_152855.3		c.*54C>G		3_prime_UTR	Exon 2 of 2	NP_690594.1	P15814-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGLL1	ENST00000330377.3	TSL:1 MANE Select	c.425C>G	p.Pro142Arg	missense	Exon 3 of 3	ENSP00000329312.2	P15814-1
	IGLL1	ENST00000249053.3	TSL:1	c.*54C>G		3_prime_UTR	Exon 2 of 2	ENSP00000249053.3	P15814-2
	IGLL1	ENST00000438703.1	TSL:2	c.428C>G	p.Pro143Arg	missense	Exon 3 of 3	ENSP00000403391.1	C9JEE0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461038 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726818

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86204

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111312

Other (OTH) AF: 0.00 AC: 0 AN: 60348

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-0.098
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.0064	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	4.8	H
PhyloP100		5.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Uncertain	0.30
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.61
MutPred		0.68		Gain of catalytic residue at P142 (P = 0.0107)
MVP		0.41
MPC		0.36
ClinPred		0.99	D
GERP RS		1.4
Varity_R		0.61
gMVP		0.75
Mutation Taster		=64/36	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: rs1064422; hg19: chr22-23915670;