rs1064422

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr22-23573483-G-A
• chr22-23573483-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_020070.4(IGLL1):​c.425C>T​(p.Pro142Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 152,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P142P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: IGLL1 NM_020070.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:4 B:1
• Conservation: PhyloP100: 5.74
• Publications: 10 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.105534405).

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>T	p.Pro142Leu	missense	Exon 3 of 3	NP_064455.1	P15814-1
	IGLL1	NM_001369906.1		c.428C>T	p.Pro143Leu	missense	Exon 3 of 3	NP_001356835.1
	IGLL1	NM_152855.3		c.*54C>T		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>T	p.Pro142Leu	missense	Exon 3 of 3	ENSP00000329312.2	P15814-1
	IGLL1	ENST00000249053.3	TSL:1	c.*54C>T		3_prime_UTR	Exon 2 of 2	ENSP00000249053.3	P15814-2
	IGLL1	ENST00000438703.1	TSL:2	c.428C>T	p.Pro143Leu	missense	Exon 3 of 3	ENSP00000403391.1	C9JEE0

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00178

Gnomad OTH AF: 0.000960

GnomAD2 exomes AF: 0.000299 AC: 75 AN: 251082 AF XY: 0.000228

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000467

Gnomad OTH exome AF: 0.000490

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000866 AC: 1264 AN: 1459548 Hom.: 1 Cov.: 33 AF XY: 0.000855 AC XY: 621 AN XY: 726092

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

African (AFR) AF: 0.000239 AC: 8 AN: 33450

American (AMR) AF: 0.000246 AC: 11 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00299 AC: 78 AN: 26106

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39694

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86176

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.000971 AC: 1078 AN: 1109954

Other (OTH) AF: 0.00109 AC: 66 AN: 60308

⚠️ 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 AF: 0.00101 AC: 154 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.000996 AC XY: 74 AN XY: 74316

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

African (AFR) AF: 0.000241 AC: 10 AN: 41454

American (AMR) AF: 0.000197 AC: 3 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3470

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00178 AC: 121 AN: 67960

Other (OTH) AF: 0.000950 AC: 2 AN: 2106

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000450 Hom.: 0

ExAC AF: 0.000214 AC: 26

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	2	-	Agammaglobulinemia 2, autosomal recessive (4)
1	-	1	not provided (2)
-	1	-	IGLL1-related condition (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-8.2	D
REVEL	Benign	0.23
Sift	Uncertain	0.014	D
Sift4G	Benign	0.062	T
Polyphen		1.0	D
Vest4		0.49
MVP		0.43
MPC		0.35
ClinPred		0.44	T
GERP RS		1.4
Varity_R		0.57
gMVP		0.73
Mutation Taster		=62/38	disease causing (ClinVar)

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; COSMIC: COSV50770279; COSMIC: COSV50770279;