Genetic Variant ZSWIM1:p.His354Gln (chr20-45883654-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080603.5(ZSWIM1):c.1062C>A(p.His354Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H354Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ZSWIM1
NM_080603.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.237

Variant links:

Genes affected

ZSWIM1 (HGNC:16155): (zinc finger SWIM-type containing 1) Predicted to enable zinc ion binding activity. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZSWIM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.012917399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZSWIM1	NM_080603.5 link	c.1062C>A	p.His354Gln	missense_variant	Exon 2 of 2	ENST00000372523.1	NP_542170.3	Q9BR11
ZSWIM1	XM_005260610.6 link	c.1062C>A	p.His354Gln	missense_variant	Exon 2 of 2		XP_005260667.1	Q9BR11
ZSWIM1	XM_005260611.5 link	c.1062C>A	p.His354Gln	missense_variant	Exon 2 of 2		XP_005260668.1	Q9BR11
ZSWIM1	XM_011529100.3 link	c.1062C>A	p.His354Gln	missense_variant	Exon 2 of 2		XP_011527402.1	Q9BR11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZSWIM1	ENST00000372523.1 link	c.1062C>A	p.His354Gln	missense_variant	Exon 2 of 2	2	NM_080603.5	ENSP00000361601.1		Q9BR11

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000147

AC:

AN:

251408

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000872

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

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1062C>A (p.H354Q) alteration is located in exon 2 (coding exon 1) of the ZSWIM1 gene. This alteration results from a C to A substitution at nucleotide position 1062, causing the histidine (H) at amino acid position 354 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.52

DANN

Benign

0.73

DEOGEN2

Benign

0.0019

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.55

.;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.013

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.3

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.29

N;N

REVEL

Benign

0.024

Sift

Benign

0.53

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0030

B;B

Vest4

0.10

MutPred

0.35

Loss of ubiquitination at K351 (P = 0.0992);Loss of ubiquitination at K351 (P = 0.0992);

MVP

0.095

MPC

0.19

ClinPred

0.0097

GERP RS

-2.1

Varity_R

0.060

gMVP

0.31

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over