chr5-61332300-C-A

Variant names:

• chr5-61332300-C-A
• rs1744264232
• NM_020928.2:c.28C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020928.2(ZSWIM6):​c.28C>A​(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000428 in 1,168,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. P10H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000039 (0 hom.)
• Consequence: ZSWIM6 NM_020928.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.833
• Publications: 0 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: 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)

ENSG00000288936 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10217586).

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.28C>A	p.Pro10Thr	missense	Exon 1 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.28C>A	p.Pro10Thr	missense	Exon 1 of 14	ENSP00000252744.5	Q9HCJ5
	ENSG00000288936	ENST00000821437.1		n.49G>T		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000288936	ENST00000821446.1		n.39G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150680 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000393 AC: 4 AN: 1017652 Hom.: 0 Cov.: 28 AF XY: 0.00000415 AC XY: 2 AN XY: 481698

African (AFR) AF: 0.00 AC: 0 AN: 20662

American (AMR) AF: 0.00 AC: 0 AN: 6004

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11540

East Asian (EAS) AF: 0.00 AC: 0 AN: 21406

South Asian (SAS) AF: 0.000157 AC: 3 AN: 19094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3604

European-Non Finnish (NFE) AF: 0.00000114 AC: 1 AN: 879822

Other (OTH) AF: 0.00 AC: 0 AN: 38984

GnomAD4 genome AF: 0.00000663 AC: 1 AN: 150788 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73708

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67502

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.83
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.070	N
REVEL	Benign	0.029
Sift	Benign	0.23	T
Sift4G	Uncertain	0.052	T
Polyphen		0.062	B
Vest4		0.24
MutPred		0.31		Gain of phosphorylation at P10 (P = 0.0117)
MVP		0.10
MPC		0.55
ClinPred		0.15	T
GERP RS		2.8
PromoterAI		0.036	Neutral
Varity_R		0.11
gMVP		0.57
Mutation Taster		=88/12	polymorphism

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: rs1744264232; hg19: chr5-60628127;