chr19-12668409-C-G

Variant names:

• chr19-12668409-C-G
• rs368657914
• NM_016145.4:c.271G>C

Variant summary

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

The NM_016145.4(WDR83OS):​c.271G>C​(p.Val91Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,344 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V91M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: WDR83OS NM_016145.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.24
• Publications: 0 publications found

Genes affected

WDR83OS (HGNC:30203): (WD repeat domain 83 opposite strand) Enables protein folding chaperone. Involved in protein insertion into ER membrane. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ENSG00000269590 (HGNC:):

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_016145.4. 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
	WDR83OS	NM_016145.4	MANE Select	c.271G>C	p.Val91Leu	missense	Exon 4 of 4	NP_057229.1	Q9Y284
	WDR83	NM_001099737.3	MANE Select	c.-156-99C>G		intron	N/A	NP_001093207.1	Q9BRX9
	WDR83	NR_029375.2		n.187-99C>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR83OS	ENST00000596731.7	TSL:1 MANE Select	c.271G>C	p.Val91Leu	missense	Exon 4 of 4	ENSP00000468969.1	Q9Y284
	WDR83	ENST00000418543.8	TSL:1 MANE Select	c.-156-99C>G		intron	N/A	ENSP00000402653.3	Q9BRX9
	ENSG00000269590	ENST00000597961.1	TSL:4	c.150+719G>C		intron	N/A	ENSP00000472710.1	M0R2P5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461344 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726904

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44608

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111800

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L
PhyloP100		5.2
PrimateAI	Pathogenic	0.82	D
REVEL	Uncertain	0.42
Sift4G	Benign	0.70	T
Polyphen		0.99	D
Vest4		0.75
MutPred		0.78		Loss of catalytic residue at V91 (P = 0.0361)
MVP		0.23
MPC		0.97
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.37
gMVP		0.86
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs368657914; hg19: chr19-12779223;