14-100376562-G-A

Variant names:

• chr14-100376562-G-A
• rs2273802
• ENST00000335290.10:c.-158G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000335290.10(WDR25):​c.-158G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,231,630 control chromosomes in the GnomAD database, including 47,085 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9165 hom., cov: 34)
  • Exomes 𝑓: 0.26 (37920 hom.)
• Consequence: WDR25 ENST00000335290.10 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.08
• Publications: 10 publications found

Genes affected

WDR25 (HGNC:21064): (WD repeat domain 25) This gene encodes a protein containing 7 WD repeats. WD repeats are approximately 30 to 40-amino acid domains containing several conserved residues, typically having a Tryptophan-Aspartic acid dipeptide (WD) at the C-terminal end. WD domains are involved in protein-protein interactions in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

WARS1 (HGNC:12729): (tryptophanyl-tRNA synthetase 1) Aminoacyl-tRNA synthetases catalyze the aminoacylation of tRNA by their cognate amino acid. Because of their central role in linking amino acids with nucleotide triplets contained in tRNAs, aminoacyl-tRNA synthetases are thought to be among the first proteins that appeared in evolution. Two forms of tryptophanyl-tRNA synthetase exist, a cytoplasmic form, named WARS, and a mitochondrial form, named WARS2. Tryptophanyl-tRNA synthetase (WARS) catalyzes the aminoacylation of tRNA(trp) with tryptophan and is induced by interferon. Tryptophanyl-tRNA synthetase belongs to the class I tRNA synthetase family. Four transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

WARS1 Gene-Disease associations (from GenCC):

• distal hereditary motor neuropathy

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, ClinGen
• neuronopathy, distal hereditary motor, type 9

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with microcephaly and speech delay, with or without brain abnormalities

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000335290.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR25	NM_001161476.3	MANE Select	c.-16+67G>A		intron	N/A	NP_001154948.1
	WDR25	NM_001350947.2		c.-263G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001337876.1
	WDR25	NM_024515.6		c.-158G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_078791.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR25	ENST00000335290.10	TSL:1	c.-158G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000334148.6
	WARS1	ENST00000355338.6	TSL:1	c.-376C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000347495.2
	WDR25	ENST00000554175.5	TSL:1	c.-158G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000450727.1

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50505 AN: 152054 Hom.: 9154 Cov.: 34

Gnomad AFR AF: 0.394

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.533

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.248

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.344

GnomAD4 exome AF: 0.256 AC: 276210 AN: 1079458 Hom.: 37920 Cov.: 35 AF XY: 0.255 AC XY: 129862 AN XY: 509574

African (AFR) AF: 0.400 AC: 9177 AN: 22964

American (AMR) AF: 0.515 AC: 4334 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 4595 AN: 14386

East Asian (EAS) AF: 0.575 AC: 15245 AN: 26528

South Asian (SAS) AF: 0.128 AC: 2488 AN: 19506

European-Finnish (FIN) AF: 0.357 AC: 7538 AN: 21104

Middle Eastern (MID) AF: 0.255 AC: 743 AN: 2914

European-Non Finnish (NFE) AF: 0.239 AC: 220010 AN: 919976

Other (OTH) AF: 0.277 AC: 12080 AN: 43664

GnomAD4 genome AF: 0.332 AC: 50552 AN: 152172 Hom.: 9165 Cov.: 34 AF XY: 0.339 AC XY: 25211 AN XY: 74412

African (AFR) AF: 0.394 AC: 16369 AN: 41512

American (AMR) AF: 0.493 AC: 7541 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1114 AN: 3468

East Asian (EAS) AF: 0.533 AC: 2754 AN: 5164

South Asian (SAS) AF: 0.144 AC: 694 AN: 4828

European-Finnish (FIN) AF: 0.366 AC: 3878 AN: 10594

Middle Eastern (MID) AF: 0.240 AC: 70 AN: 292

European-Non Finnish (NFE) AF: 0.254 AC: 17244 AN: 67994

Other (OTH) AF: 0.345 AC: 730 AN: 2114

Alfa AF: 0.294 Hom.: 2138

Bravo AF: 0.353

Asia WGS AF: 0.359 AC: 1246 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.92
DANN	Benign	0.85
PhyloP100		-2.1
PromoterAI		-0.011	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2273802; hg19: chr14-100842899;