rs1064424

Variant names:

• chr22-23573515-A-G
• rs1064424
• NM_020070.4:c.393T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000330377.3(IGLL1):​c.393T>C​(p.Ala131Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,609,380 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: IGLL1 ENST00000330377.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.35
• Publications: 3 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: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000224277 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 22-23573515-A-G is Benign according to our data. Variant chr22-23573515-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 538829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000330377.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGLL1	NM_020070.4	MANE Select	c.393T>C	p.Ala131Ala	synonymous	Exon 3 of 3	NP_064455.1
	IGLL1	NM_001369906.1		c.396T>C	p.Ala132Ala	synonymous	Exon 3 of 3	NP_001356835.1
	IGLL1	NM_152855.3		c.*22T>C		3_prime_UTR	Exon 2 of 2	NP_690594.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IGLL1	ENST00000330377.3	TSL:1 MANE Select	c.393T>C	p.Ala131Ala	synonymous	Exon 3 of 3	ENSP00000329312.2
	IGLL1	ENST00000249053.3	TSL:1	c.*22T>C		3_prime_UTR	Exon 2 of 2	ENSP00000249053.3
	IGLL1	ENST00000438703.1	TSL:2	c.396T>C	p.Ala132Ala	synonymous	Exon 3 of 3	ENSP00000403391.1

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000533

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00225

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00168 AC: 420 AN: 250272 AF XY: 0.00159

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00201

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00128

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00184 AC: 2683 AN: 1457412 Hom.: 4 Cov.: 33 AF XY: 0.00183 AC XY: 1327 AN XY: 725086

African (AFR) AF: 0.000630 AC: 21 AN: 33340

American (AMR) AF: 0.00110 AC: 49 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0163 AC: 425 AN: 26036

East Asian (EAS) AF: 0.00239 AC: 95 AN: 39690

South Asian (SAS) AF: 0.000731 AC: 63 AN: 86200

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53384

Middle Eastern (MID) AF: 0.000696 AC: 4 AN: 5748

European-Non Finnish (NFE) AF: 0.00167 AC: 1852 AN: 1108110

Other (OTH) AF: 0.00266 AC: 160 AN: 60226

GnomAD4 genome AF: 0.00186 AC: 282 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74318

African (AFR) AF: 0.000531 AC: 22 AN: 41416

American (AMR) AF: 0.00144 AC: 22 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3468

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5176

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4818

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00225 AC: 153 AN: 67896

Other (OTH) AF: 0.00332 AC: 7 AN: 2110

Alfa AF: 0.00400 Hom.: 2

Bravo AF: 0.00183

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Agammaglobulinemia 2, autosomal recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	7.1
DANN	Benign	0.39
PhyloP100		1.4
Mutation Taster		=99/1	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: rs1064424; hg19: chr22-23915702;