Genetic Variant ZSWIM6:p.Met1? (chr5-61332274-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_020928.2(ZSWIM6):c.2T>C(p.Met1?) variant causes a start lost 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZSWIM6
NM_020928.2 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.78

Publications

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

ZSWIM6 links:

ENSG00000288936 (HGNC:):

ENSG00000288936 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 123 codons. Genomic position: 61332639. Lost 0.101 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

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.2T>C	p.Met1?	start_lost	Exon 1 of 14	NP_065979.1	Q9HCJ5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZSWIM6	ENST00000252744.6	TSL:5 MANE Select	c.2T>C	p.Met1?	start_lost	Exon 1 of 14	ENSP00000252744.5	Q9HCJ5
ENSG00000288936	ENST00000821437.1		n.75A>G		non_coding_transcript_exon	Exon 1 of 2
ENSG00000288936	ENST00000821446.1		n.65A>G		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1009914

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

476146

African (AFR)

AF:

0.00

AC:

AN:

20518

American (AMR)

AF:

0.00

AC:

AN:

5888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11428

East Asian (EAS)

AF:

0.00

AC:

AN:

20918

South Asian (SAS)

AF:

0.00

AC:

AN:

18958

European-Finnish (FIN)

AF:

0.00

AC:

AN:

16568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

873362

Other (OTH)

AF:

0.00

AC:

AN:

38518

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0011

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.012

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-1.0

PhyloP100

1.8

PROVEAN

Benign

-0.53

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0030

Polyphen

0.017

Vest4

0.94

MutPred

0.96

Gain of phosphorylation at M1 (P = 0.0097)

MVP

0.10

ClinPred

0.57

GERP RS

2.3

PromoterAI

-0.29

Neutral

(source)

Varity_R

0.89

gMVP

0.77

Mutation Taster

=21/179

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over