rs565314713

Variant names:

• chr22-22888172-G-A
• rs565314713
• NM_001178126.2:c.119G>A

Your query was ambiguous. Multiple possible variants found:

• chr22-22888172-G-A
• chr22-22888172-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001178126.2(IGLL5):​c.119G>A​(p.Arg40His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000254 in 1,549,092 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R40C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0012 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: IGLL5 NM_001178126.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.942

Genes affected

IGLL5 (HGNC:38476): (immunoglobulin lambda like polypeptide 5) This gene encodes one of the immunoglobulin lambda-like polypeptides. It is located within the immunoglobulin lambda locus but it does not require somatic rearrangement for expression. The first exon of this gene is unrelated to immunoglobulin variable genes; the second and third exons are the immunoglobulin lambda joining 1 and the immunoglobulin lambda constant 1 gene segments. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

IGL (HGNC:5853):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045471787).
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IGLL5	NM_001178126.2	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	ENST00000526893.6	NP_001171597.1
IGLL5	NM_001256296.2	c.13G>A	p.Ala5Thr	missense_variant	Exon 1 of 2		NP_001243225.1
IGL		n.22888172G>A		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IGLL5	ENST00000526893.6	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	1	NM_001178126.2	ENSP00000431254.1
IGLL5	ENST00000532223.2	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 3	1		ENSP00000436353.1
IGLL5	ENST00000531372.1	c.119G>A	p.Arg40His	missense_variant	Exon 1 of 2	1		ENSP00000434368.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 172 AN: 151142 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00145

GnomAD2 exomes AF: 0.000341 AC: 50 AN: 146640 AF XY: 0.000278

Gnomad AFR exome AF: 0.00489

Gnomad AMR exome AF: 0.000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000157 AC: 219 AN: 1397840 Hom.: 1 Cov.: 32 AF XY: 0.000133 AC XY: 92 AN XY: 689464

African (AFR) AF: 0.00370 AC: 117 AN: 31600

American (AMR) AF: 0.000392 AC: 14 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25128

East Asian (EAS) AF: 0.000308 AC: 11 AN: 35750

South Asian (SAS) AF: 0.0000884 AC: 7 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48186

Middle Eastern (MID) AF: 0.000362 AC: 2 AN: 5530

European-Non Finnish (NFE) AF: 0.0000491 AC: 53 AN: 1078770

Other (OTH) AF: 0.000259 AC: 15 AN: 57966

GnomAD4 genome AF: 0.00115 AC: 174 AN: 151252 Hom.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 84 AN XY: 73864

African (AFR) AF: 0.00392 AC: 162 AN: 41304

American (AMR) AF: 0.000132 AC: 2 AN: 15122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 4870

South Asian (SAS) AF: 0.00 AC: 0 AN: 4746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67854

Other (OTH) AF: 0.00143 AC: 3 AN: 2098

Alfa AF: 0.000734 Hom.: 0

Bravo AF: 0.00127

ExAC AF: 0.000222 AC: 16

Asia WGS AF: 0.000581 AC: 2 AN: 3452

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.119G>A (p.R40H) alteration is located in exon 1 (coding exon 1) of the IGLL5 gene. This alteration results from a G to A substitution at nucleotide position 119, causing the arginine (R) at amino acid position 40 to be replaced by a histidine (H). 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	0.083
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	6.1
DANN	Benign	0.93
DEOGEN2	Benign	0.0024	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.36	T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.0045	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;.;N
PhyloP100		-0.94
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.053
MVP		0.014
ClinPred		0.00087	T
GERP RS		-2.3
PromoterAI		-0.017	Neutral
Varity_R		0.020
gMVP		0.073
Mutation Taster		=94/6	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

Publications

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Other links and lift over

dbSNP: rs565314713; hg19: chr22-23230352; COSMIC: COSV73250778; COSMIC: COSV73250778;