5-61332333-GGCGGCGGCGGCGGGGGCAGCA-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_020928.2(ZSWIM6):c.75_95del(p.Ser27_Gly33del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,055,464 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: ZSWIM6 NM_020928.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.10

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 5-61332333-GGCGGCGGCGGCGGGGGCAGCA-G is Benign according to our data. Variant chr5-61332333-GGCGGCGGCGGCGGGGGCAGCA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1474417.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZSWIM6	NM_020928.2	c.75_95del	p.Ser27_Gly33del	inframe_deletion	1/14	ENST00000252744.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZSWIM6	ENST00000252744.6	c.75_95del	p.Ser27_Gly33del	inframe_deletion	1/14	5	NM_020928.2	P1

Frequencies

GnomAD3 genomes AF: 0.000446 AC: 59 AN: 132364 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000766

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000511

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000563 AC: 52 AN: 923030 Hom.: 0 AF XY: 0.0000666 AC XY: 29 AN XY: 435746

Gnomad4 AFR exome AF: 0.00109

Gnomad4 AMR exome AF: 0.000637

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000391

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000872

Gnomad4 OTH exome AF: 0.000376

GnomAD4 genome AF: 0.000446 AC: 59 AN: 132434 Hom.: 0 Cov.: 31 AF XY: 0.000530 AC XY: 34 AN XY: 64188

Gnomad4 AFR AF: 0.00119

Gnomad4 AMR AF: 0.000464

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000769

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000511

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1474417). This variant has not been reported in the literature in individuals affected with ZSWIM6-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.75_95del, results in the deletion of 7 amino acid(s) of the ZSWIM6 protein (p.Ser27_Gly33del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1243690822; hg19: chr5-60628160;