11-62833013-G-A

Position:

• chr11-62833013-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001369450.1(WDR74):​c.1097C>T​(p.Pro366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,610,644 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0093 (20 hom., cov: 30)
  • Exomes 𝑓: 0.00095 (29 hom.)
• Consequence: WDR74 NM_001369450.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.106

Genes affected

WDR74 (HGNC:25529): (WD repeat domain 74) Involved in rRNA processing and ribosomal large subunit biogenesis. Located in nucleoplasm. Colocalizes with nuclear exosome (RNase complex) and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

STX5-DT (HGNC:55488): (STX5 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023863316).
• BP6: Variant 11-62833013-G-A is Benign according to our data. Variant chr11-62833013-G-A is described in ClinVar as [Benign]. Clinvar id is 780997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00929 (1413/152082) while in subpopulation AFR AF= 0.0324 (1345/41456). AF 95% confidence interval is 0.031. There are 20 homozygotes in gnomad4. There are 641 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WDR74	NM_001369450.1	c.1097C>T	p.Pro366Leu	missense_variant	11/11	ENST00000278856.9
STX5-DT	NR_135084.1	n.85-550G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WDR74	ENST00000278856.9	c.1097C>T	p.Pro366Leu	missense_variant	11/11	1	NM_001369450.1	P1
STX5-DT	ENST00000535817.1	n.85-550G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00931 AC: 1415 AN: 151964 Hom.: 20 Cov.: 30

Gnomad AFR AF: 0.0326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00315

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00671

GnomAD3 exomes AF: 0.00228 AC: 544 AN: 239078 Hom.: 6 AF XY: 0.00160 AC XY: 209 AN XY: 130240

Gnomad AFR exome AF: 0.0327

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000650

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.000952 AC: 1389 AN: 1458562 Hom.: 29 Cov.: 31 AF XY: 0.000800 AC XY: 580 AN XY: 725326

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.00186

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00929 AC: 1413 AN: 152082 Hom.: 20 Cov.: 30 AF XY: 0.00862 AC XY: 641 AN XY: 74362

Gnomad4 AFR AF: 0.0324

Gnomad4 AMR AF: 0.00314

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00168 Hom.: 2

Bravo AF: 0.0109

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0319 AC: 118

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00274 AC: 331

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.78
DEOGEN2	Benign	0.0034	.;T;T;T;T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.50	T;T;.;.;T
MetaRNN	Benign	0.0024	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N;N;N;N;N
REVEL	Benign	0.078
Sift	Benign	0.37	T;T;T;T;T
Sift4G	Benign	0.43	T;T;T;T;T
Polyphen		0.0	B;B;B;B;B
Vest4		0.13
MVP		0.39
MPC		0.35
ClinPred		0.00060	T
GERP RS		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs115081668; hg19: chr11-62600485;