5-61332325-C-A

Variant names:

• chr5-61332325-C-A
• rs1744264776
• NM_020928.2:c.53C>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.53C>A​(p.Pro18Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000995 in 1,004,570 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P18L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: ZSWIM6 NM_020928.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.80
• 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: ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• 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=0.18391621).

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.53C>A	p.Pro18Gln	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.53C>A	p.Pro18Gln	missense	Exon 1 of 14	ENSP00000252744.5	Q9HCJ5
	ENSG00000288936	ENST00000821437.1		n.24G>T		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000288936	ENST00000821446.1		n.14G>T		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.95e-7 AC: 1 AN: 1004570 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 475196

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20236

American (AMR) AF: 0.00 AC: 0 AN: 5634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11100

East Asian (EAS) AF: 0.00 AC: 0 AN: 20148

South Asian (SAS) AF: 0.00 AC: 0 AN: 18962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2976

European-Non Finnish (NFE) AF: 0.00000115 AC: 1 AN: 872112

Other (OTH) AF: 0.00 AC: 0 AN: 38132

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.0073	N
LIST_S2	Benign	0.46	T
M_CAP	Pathogenic	0.47	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.8
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.055
Sift	Uncertain	0.024	D
Sift4G	Benign	0.13	T
Polyphen		0.022	B
Vest4		0.26
MutPred		0.30		Gain of MoRF binding (P = 0.0446)
MVP		0.067
MPC		0.46
ClinPred		0.44	T
GERP RS		3.2
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.43
Mutation Taster		=67/33	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: rs1744264776; hg19: chr5-60628152;