chr5-111111204-A-G

Variant names:

• chr5-111111204-A-G
• rs34661294
• NM_139281.3:c.1642A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_139281.3(WDR36):​c.1642A>G​(p.Ile548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000961 in 1,611,944 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0053 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (10 hom.)
• Consequence: WDR36 NM_139281.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.33
• Publications: 5 publications found

Genes affected

WDR36 (HGNC:30696): (WD repeat domain 36) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Mutations in this gene have been associated with adult-onset primary open-angle glaucoma (POAG). [provided by RefSeq, Jul 2008]

WDR36 Gene-Disease associations (from GenCC):

• glaucoma 1, open angle, G

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007596582).
• BP6: Variant 5-111111204-A-G is Benign according to our data. Variant chr5-111111204-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 350319.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00525 (797/151742) while in subpopulation AFR AF = 0.018 (749/41506). AF 95% confidence interval is 0.017. There are 15 homozygotes in GnomAd4. There are 394 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 797 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139281.3. 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
	WDR36	NM_139281.3	MANE Select	c.1642A>G	p.Ile548Val	missense	Exon 15 of 23	NP_644810.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR36	ENST00000513710.4	TSL:1 MANE Select	c.1642A>G	p.Ile548Val	missense	Exon 15 of 23	ENSP00000424628.3
	WDR36	ENST00000946910.1		c.1642A>G	p.Ile548Val	missense	Exon 15 of 23	ENSP00000616969.1
	WDR36	ENST00000856283.1		c.1639A>G	p.Ile547Val	missense	Exon 15 of 23	ENSP00000526342.1

Frequencies

GnomAD3 genomes AF: 0.00525 AC: 796 AN: 151624 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00432

GnomAD2 exomes AF: 0.00136 AC: 342 AN: 251162 AF XY: 0.000936

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000515 AC: 752 AN: 1460202 Hom.: 10 Cov.: 31 AF XY: 0.000449 AC XY: 326 AN XY: 726400

African (AFR) AF: 0.0193 AC: 646 AN: 33406

American (AMR) AF: 0.000984 AC: 44 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110662

Other (OTH) AF: 0.000895 AC: 54 AN: 60308

GnomAD4 genome AF: 0.00525 AC: 797 AN: 151742 Hom.: 15 Cov.: 32 AF XY: 0.00531 AC XY: 394 AN XY: 74188

African (AFR) AF: 0.0180 AC: 749 AN: 41506

American (AMR) AF: 0.00204 AC: 31 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67692

Other (OTH) AF: 0.00428 AC: 9 AN: 2104

Alfa AF: 0.00345 Hom.: 0

Bravo AF: 0.00623

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	Primary open angle glaucoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.77	N
PhyloP100		2.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.35	N
REVEL	Uncertain	0.32
Sift4G	Benign	0.54	T
Polyphen		0.013	B
Vest4		0.75
MVP		0.55
MPC		0.027
ClinPred		0.0051	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.087
gMVP		0.29
Mutation Taster		=85/15	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: rs34661294; hg19: chr5-110446903;