16-70656644-G-A

Variant names:

• chr16-70656644-G-A
• rs763664931
• NM_001393494.1:c.205G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393494.1(IL34):​c.205G>A​(p.Glu69Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 1,320,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IL34 NM_001393494.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52
• Publications: 1 publications found

Genes affected

IL34 (HGNC:28529): (interleukin 34) Interleukin-34 is a cytokine that promotes the differentiation and viability of monocytes and macrophages through the colony-stimulating factor-1 receptor (CSF1R; MIM 164770) (Lin et al., 2008 [PubMed 18467591]).[supplied by OMIM, May 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393494.1. 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
	IL34	NM_001393494.1	MANE Select	c.205G>A	p.Glu69Lys	missense	Exon 3 of 6	NP_001380423.1	Q6ZMJ4-1
	IL34	NM_001172772.2		c.205G>A	p.Glu69Lys	missense	Exon 4 of 7	NP_001166243.1	Q6ZMJ4-1
	IL34	NM_001393493.1		c.205G>A	p.Glu69Lys	missense	Exon 4 of 7	NP_001380422.1	Q6ZMJ4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IL34	ENST00000288098.7	TSL:1 MANE Select	c.205G>A	p.Glu69Lys	missense	Exon 3 of 6	ENSP00000288098.2	Q6ZMJ4-1
	IL34	ENST00000566361.1	TSL:1	c.130G>A	p.Glu44Lys	missense	Exon 3 of 6	ENSP00000463886.1	J3QQT3
	IL34	ENST00000429149.6	TSL:5	c.205G>A	p.Glu69Lys	missense	Exon 4 of 7	ENSP00000397863.2	Q6ZMJ4-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000795 AC: 2 AN: 251450 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000454 AC: 6 AN: 1320840 Hom.: 0 Cov.: 24 AF XY: 0.00000902 AC XY: 6 AN XY: 664840

African (AFR) AF: 0.00 AC: 0 AN: 30740

American (AMR) AF: 0.00 AC: 0 AN: 44548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25212

East Asian (EAS) AF: 0.00 AC: 0 AN: 39038

South Asian (SAS) AF: 0.0000599 AC: 5 AN: 83418

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5482

European-Non Finnish (NFE) AF: 0.00000102 AC: 1 AN: 983230

Other (OTH) AF: 0.00 AC: 0 AN: 55806

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2088

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.011	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.68
MutPred		0.49		Gain of MoRF binding (P = 0.0013)
MVP		0.77
MPC		0.21
ClinPred		0.94	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.59
Mutation Taster		=65/35	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: rs763664931; hg19: chr16-70690547; COSMIC: COSV105160464; COSMIC: COSV105160464;