rs116036211

chr5-61526288-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_020928.2(ZSWIM6):c.1729C>T(p.Arg577Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,551,816 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: ZSWIM6 NM_020928.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.42

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 Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ZSWIM6
• BP4: Computational evidence support a benign effect (MetaRNN=0.017198443).
• BP6: Variant 5-61526288-C-T is Benign according to our data. Variant chr5-61526288-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 599455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-61526288-C-T is described in Lovd as [Likely_benign]. Variant chr5-61526288-C-T is described in Lovd as [Benign].
• BS2: High AC in GnomAd at 527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSWIM6	NM_020928.2	c.1729C>T	p.Arg577Cys	missense_variant	7/14	ENST00000252744.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSWIM6	ENST00000252744.6	c.1729C>T	p.Arg577Cys	missense_variant	7/14	5	NM_020928.2	P1

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00619

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00286 AC: 450 AN: 157472 Hom.: 2 AF XY: 0.00280 AC XY: 233 AN XY: 83166

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00119

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.00569

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00538 AC: 7534 AN: 1399562 Hom.: 28 Cov.: 31 AF XY: 0.00523 AC XY: 3607 AN XY: 690280

Gnomad4 AFR exome AF: 0.000981

Gnomad4 AMR exome AF: 0.00227

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.000304

Gnomad4 NFE exome AF: 0.00654

Gnomad4 OTH exome AF: 0.00431

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152254 Hom.: 1 Cov.: 32 AF XY: 0.00318 AC XY: 237 AN XY: 74438

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00620

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00531 Hom.: 6

Bravo AF: 0.00345

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00534 AC: 17

ExAC AF: 0.00178 AC: 45

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	ZSWIM6: BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Apr 19, 2017

BS1,BS2; This alteration has an allele frequency that is greater than expected for the associated disease, and was seen in a healthy adult where full penetrance of the disorder is expected at an early age. -

ZSWIM6-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.23	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.017	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.70
MVP		0.77
MPC		1.1
ClinPred		0.060	T
GERP RS		4.7
Varity_R		0.73
gMVP		0.82

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: rs116036211; hg19: chr5-60822115; COSMIC: COSV53178402;