NM_015045.5:c.370G>A

Variant names:

• chr10-86517700-C-T
• rs10887621
• NM_015045.5:c.370G>A

Variant summary

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

The NM_015045.5(WAPL):​c.370G>A​(p.Val124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,938 control chromosomes in the GnomAD database, including 58,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.21 (4021 hom., cov: 33)
  • Exomes 𝑓: 0.27 (54318 hom.)
• Consequence: WAPL NM_015045.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.52
• Publications: 24 publications found

Genes affected

WAPL (HGNC:23293): (WAPL cohesin release factor) Involved in several processes, including negative regulation of DNA replication; negative regulation of chromatin binding activity; and regulation of sister chromatid cohesion. Located in several cellular components, including Golgi apparatus; intercellular bridge; and microtubule cytoskeleton. [provided by Alliance of Genome Resources, Apr 2022]

WAPL Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038123429).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.326 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015045.5. 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
	WAPL	NM_015045.5	MANE Select	c.370G>A	p.Val124Ile	missense	Exon 2 of 19	NP_055860.1
	WAPL	NM_001318328.2		c.370G>A	p.Val124Ile	missense	Exon 2 of 19	NP_001305257.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAPL	ENST00000298767.10	TSL:1 MANE Select	c.370G>A	p.Val124Ile	missense	Exon 2 of 19	ENSP00000298767.4

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32204 AN: 152014 Hom.: 4022 Cov.: 33

Gnomad AFR AF: 0.0940

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.174

GnomAD2 exomes AF: 0.241 AC: 60653 AN: 251340 AF XY: 0.253

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.0996

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.274

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.267 AC: 389965 AN: 1461806 Hom.: 54318 Cov.: 36 AF XY: 0.270 AC XY: 196679 AN XY: 727206

African (AFR) AF: 0.0898 AC: 3007 AN: 33476

American (AMR) AF: 0.105 AC: 4675 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 6568 AN: 26132

East Asian (EAS) AF: 0.169 AC: 6710 AN: 39686

South Asian (SAS) AF: 0.350 AC: 30227 AN: 86254

European-Finnish (FIN) AF: 0.293 AC: 15621 AN: 53404

Middle Eastern (MID) AF: 0.201 AC: 1157 AN: 5766

European-Non Finnish (NFE) AF: 0.276 AC: 307066 AN: 1111970

Other (OTH) AF: 0.247 AC: 14934 AN: 60394

GnomAD4 genome AF: 0.212 AC: 32203 AN: 152132 Hom.: 4021 Cov.: 33 AF XY: 0.214 AC XY: 15884 AN XY: 74368

African (AFR) AF: 0.0938 AC: 3898 AN: 41536

American (AMR) AF: 0.126 AC: 1932 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3472

East Asian (EAS) AF: 0.198 AC: 1028 AN: 5186

South Asian (SAS) AF: 0.339 AC: 1635 AN: 4820

European-Finnish (FIN) AF: 0.304 AC: 3199 AN: 10538

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.278 AC: 18907 AN: 67978

Other (OTH) AF: 0.172 AC: 364 AN: 2112

Alfa AF: 0.249 Hom.: 17394

Bravo AF: 0.189

TwinsUK AF: 0.272 AC: 1007

ALSPAC AF: 0.278 AC: 1073

ESP6500AA AF: 0.105 AC: 462

ESP6500EA AF: 0.282 AC: 2426

ExAC AF: 0.247 AC: 30049

EpiCase AF: 0.262

EpiControl AF: 0.255

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.11	N
REVEL	Benign	0.080
Sift	Benign	0.089	T
Sift4G	Benign	0.40	T
Polyphen		0.014	B
Vest4		0.012
MPC		0.14
ClinPred		0.0013	T
GERP RS		1.1
Varity_R		0.033
gMVP		0.11
Mutation Taster		=99/1	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: rs10887621; hg19: chr10-88277457; COSMIC: COSV53935627; COSMIC: COSV53935627;