chr11-62833934-C-T

Variant names:

• chr11-62833934-C-T
• rs370706053
• NM_001369450.1:c.779G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001369450.1(WDR74):​c.779G>A​(p.Arg260His) variant causes a missense change. The variant allele was found at a frequency of 0.0000998 in 1,613,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R260C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000098 (0 hom.)
• Consequence: WDR74 NM_001369450.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.31
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13547435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369450.1. 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
	WDR74	NM_001369450.1	MANE Select	c.779G>A	p.Arg260His	missense	Exon 9 of 11	NP_001356379.1	Q6RFH5-1
	WDR74	NM_001369447.1		c.821G>A	p.Arg274His	missense	Exon 9 of 11	NP_001356376.1
	WDR74	NM_001369451.1		c.779G>A	p.Arg260His	missense	Exon 10 of 12	NP_001356380.1	Q6RFH5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR74	ENST00000278856.9	TSL:1 MANE Select	c.779G>A	p.Arg260His	missense	Exon 9 of 11	ENSP00000278856.4	Q6RFH5-1
	WDR74	ENST00000311713.11	TSL:1	c.779G>A	p.Arg260His	missense	Exon 9 of 10	ENSP00000308931.7	Q6RFH5-2
	WDR74	ENST00000892916.1		c.821G>A	p.Arg274His	missense	Exon 10 of 12	ENSP00000562975.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152190 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000105 AC: 26 AN: 248420 AF XY: 0.0000965

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000979 AC: 143 AN: 1461148 Hom.: 0 Cov.: 31 AF XY: 0.0000963 AC XY: 70 AN XY: 726844

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.000134 AC: 6 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86216

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53314

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5764

European-Non Finnish (NFE) AF: 0.0000882 AC: 98 AN: 1111596

Other (OTH) AF: 0.000215 AC: 13 AN: 60348

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152190 Hom.: 0 Cov.: 31 AF XY: 0.000108 AC XY: 8 AN XY: 74354

African (AFR) AF: 0.000193 AC: 8 AN: 41438

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000119 Hom.: 0

ESP6500AA AF: 0.000254 AC: 1

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000178

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	Benign	0.086
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.076
Sift	Benign	0.10	T
Sift4G	Benign	0.20	T
Polyphen		0.53	P
Vest4		0.43
MVP		0.31
MPC		0.47
ClinPred		0.024	T
GERP RS		3.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.067
gMVP		0.31
Mutation Taster		=91/9	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: rs370706053; hg19: chr11-62601406; COSMIC: COSV104378165; COSMIC: COSV104378165;