19-12669199-A-T

Variant names:

• chr19-12669199-A-T
• rs61748346
• NM_016145.4:c.85T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016145.4(WDR83OS):​c.85T>A​(p.Leu29Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,112 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: WDR83OS NM_016145.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.40

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]

ENSG00000269590 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20740008).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WDR83OS	NM_016145.4	c.85T>A	p.Leu29Met	missense_variant	Exon 2 of 4	ENST00000596731.7	NP_057229.1
WDR83	NM_001099737.3	c.-36-556A>T		intron_variant	Intron 2 of 10	ENST00000418543.8	NP_001093207.1
WDR83	NR_029375.2	n.307-556A>T		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WDR83OS	ENST00000596731.7	c.85T>A	p.Leu29Met	missense_variant	Exon 2 of 4	1	NM_016145.4	ENSP00000468969.1
ENSG00000269590	ENST00000597961.1	c.79T>A	p.Leu27Met	missense_variant	Exon 2 of 5	4		ENSP00000472710.1
WDR83	ENST00000418543.8	c.-36-556A>T		intron_variant	Intron 2 of 10	1	NM_001099737.3	ENSP00000402653.3
ENSG00000285589	ENST00000648033.1	n.*4019T>A		non_coding_transcript_exon_variant	Exon 12 of 14			ENSP00000498000.1
ENSG00000285589	ENST00000648033.1	n.*4019T>A		3_prime_UTR_variant	Exon 12 of 14			ENSP00000498000.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152112 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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152112 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	.;T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	.;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.17	.;.;N
REVEL	Benign	0.17
Sift	Benign	0.26	.;.;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.78	.;P;.
Vest4		0.47, 0.46
MutPred		0.29		.;Gain of disorder (P = 0.0838);Gain of disorder (P = 0.0838);
MVP		0.15
MPC		0.79
ClinPred		0.71	D
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61748346; hg19: chr19-12780013;