10-86446384-A-C

Variant names:

• chr10-86446384-A-C
• NM_015045.5:c.3180T>G
• WAPL p.Asp1060Glu

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015045.5(WAPL):​c.3180T>G​(p.Asp1060Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WAPL NM_015045.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.524
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052811086).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAPL	NM_015045.5	MANE Select	c.3180T>G	p.Asp1060Glu	missense	Exon 16 of 19	NP_055860.1	Q7Z5K2-1
	WAPL	NM_001318328.2		c.3162T>G	p.Asp1054Glu	missense	Exon 16 of 19	NP_001305257.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WAPL	ENST00000298767.10	TSL:1 MANE Select	c.3180T>G	p.Asp1060Glu	missense	Exon 16 of 19	ENSP00000298767.4	Q7Z5K2-1
	WAPL	ENST00000920312.1		c.3258T>G	p.Asp1086Glu	missense	Exon 17 of 20	ENSP00000590371.1
	WAPL	ENST00000910171.1		c.3198T>G	p.Asp1066Glu	missense	Exon 16 of 19	ENSP00000580230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.44
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.42	N
PhyloP100		0.52
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.11
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Varity_R		0.053
gMVP		0.042
Mutation Taster		=82/18	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr10-88206141;