dbSNP rs1554041295: ZSWIM6:p.Arg913* (chr5-61541917-C-T) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_020928.2(ZSWIM6):c.2737C>T(p.Arg913*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZSWIM6
NM_020928.2 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 3.12

Publications

2 publications found

Variant links:

Genes affected

ZSWIM6 (HGNC:29316): (zinc finger SWIM-type containing 6) The protein encoded by this gene contains a zinc finger SWI2/SNF2 and MuDR (SWIM) domain. Proteins with SWIM domains have been found in a diverse number of species and are predicted to interact with DNA or proteins. Mutations in this gene result in acromelic frontonasal dysostosis. [provided by RefSeq, Apr 2017]

ZSWIM6 Gene-Disease associations (from GenCC):

acromelic frontonasal dysostosis
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ZSWIM6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.25 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-61541917-C-T is Pathogenic according to our data. Variant chr5-61541917-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 431797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM6	NM_020928.2 link	c.2737C>T	p.Arg913*	stop_gained	Exon 13 of 14	ENST00000252744.6	NP_065979.1	Q9HCJ5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM6	ENST00000252744.6 link	c.2737C>T	p.Arg913*	stop_gained	Exon 13 of 14	5	NM_020928.2	ENSP00000252744.5		Q9HCJ5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1398236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689590

African (AFR)

AF:

0.00

AC:

AN:

31590

American (AMR)

AF:

0.00

AC:

AN:

35686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

35698

South Asian (SAS)

AF:

0.00

AC:

AN:

79068

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077864

Other (OTH)

AF:

0.00

AC:

AN:

58088

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features

Pathogenic:5

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 09, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 20, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been previously reported as de novo in a similarly affected individual (PMID: 29198722). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000431797 /PMID: 29198722). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Pathogenic:4

Aug 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg913*) in the ZSWIM6 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in ZSWIM6 cause disease. This variant has been observed to be likely or confirmed de novo in multiple individuals affected with severe-profound intellectual disability/developmental delay and additional neurological features, but without frontonasal or limb malformations¬†(PMID: 29198722, Invitae). ClinVar contains an entry for this variant (Variation ID:¬†431797). This variant is not present in population databases (ExAC no frequency). Experimental studies have shown that this nonsense change does not trigger nonsense-mediated decay of the ZSWIM6 mRNA. This suggests a truncated ZSWIM6 protein lacking the Sin3-like domain exists, which may have a dominant-negative effect.¬†(PMID: 29198722). -

Jan 31, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); Not observed in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 303 amino acids are lost; This variant is associated with the following publications: (PMID: 29198722, 33958584, 34758253) -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 05, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ZWIM6 c.2737C>T; p.Arg913Ter variant (rs1554041295, ClinVar Variation ID: 431797), is a recurrent pathogenic variant reported in the literature in at least eight unrelated affected individuals and has been primarily observed to occur de novo (Palmer 2017, Yanagishita 2021). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant induces an early termination codon in the penultimate exon of the ZSWIM6 gene. Transcriptional assays suggest this does not lead to nonsense mediated decay but is predicted to result in a truncated ZSWIM6 protein (Palmer 2017). Based on available information, this variant is considered to be pathogenic. References: Palmer EE et al. A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations. Am J Hum Genet. 2017 Dec 7;101(6):995-1005. PMID: 29198722. Yanagishita T et al. A recurrent de novo ZSWIM6 variant in a Japanese patient with severe neurodevelopmental delay and frequent vomiting. Hum Genome Var. 2021 May 6;8(1):16. PMID: 33958584. -

ZSWIM6 related intellectual disability

Pathogenic:1

Aug 11, 2017

Sydney Children's Hospital, SCHN

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

De novo. Recurrent in 7 individuals with overlapping neurocognitive phenotype. Gene expressed in brain and role in neurodevelopment and function. -

ZSWIM6-related disorder

Pathogenic:1

Apr 29, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ZSWIM6 c.2737C>T variant is predicted to result in premature protein termination (p.Arg913*). This variant has been reported as a recurrent de novo variant in multiple patients with syndromic intellectual disability (see for example - Palmer et al. 2017. PubMed ID: 29198722). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the penultimate exon and functional studies found it does not undergo nonsense mediated decay and may act in a dominant-negative manner (Palmer et al. 2017. PubMed ID: 29198722). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.96

PhyloP100

3.1

Vest4

0.45

GERP RS

5.9

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over