chr5-61541917-C-T

Variant names:

• chr5-61541917-C-T
• rs1554041295
• NM_020928.2:c.2737C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_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 (★★). ClinVar reports functional evidence for this variant: "SCV000890451: Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017)" and additional evidence is available in ClinVar.

• 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:12
• Conservation: PhyloP100: 3.12
• Publications: 2 publications found

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: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 18 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000890451: Published functional studies demonstrate a dominant-negative effect on the protein (Palmer et al., 2017); SCV000958315: 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).; SCV004104534: "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)."
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020928.2. 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
	ZSWIM6	NM_020928.2	MANE Select	c.2737C>T	p.Arg913*	stop_gained	Exon 13 of 14	NP_065979.1	Q9HCJ5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZSWIM6	ENST00000252744.6	TSL:5 MANE Select	c.2737C>T	p.Arg913*	stop_gained	Exon 13 of 14	ENSP00000252744.5	Q9HCJ5

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

African (AFR) AF: 0.00 AC: 0 AN: 31590

American (AMR) AF: 0.00 AC: 0 AN: 35686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25108

East Asian (EAS) AF: 0.00 AC: 0 AN: 35698

South Asian (SAS) AF: 0.00 AC: 0 AN: 79068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077864

Other (OTH) AF: 0.00 AC: 0 AN: 58088

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (5)
4	-	-	not provided (4)
1	-	-	Inborn genetic diseases (1)
1	-	-	ZSWIM6 related intellectual disability (1)
1	-	-	ZSWIM6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.1
Vest4		0.45
GERP RS		5.9
Mutation Taster		=5/195	disease causing (ClinVar)

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