5-61541917-C-T

Position:

• chr5-61541917-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_020928.2(ZSWIM6):​c.2737C>T​(p.Arg913Ter) 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 3.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 431797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSWIM6	NM_020928.2	c.2737C>T	p.Arg913Ter	stop_gained	13/14	ENST00000252744.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSWIM6	ENST00000252744.6	c.2737C>T	p.Arg913Ter	stop_gained	13/14	5	NM_020928.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398236 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689590

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 09, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 2018	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. This variant is not present in population databases (ExAC no frequency). 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). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

ZSWIM6 related intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Sydney Children's Hospital, SCHN

Aug 11, 2017

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2023

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	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	43
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D
Vest4		0.45
GERP RS		5.9

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

LitVar

Other links and lift over

dbSNP: rs1554041295; hg19: chr5-60837744; COSMIC: COSV99404428;