7-100024305-G-A

Variant names:

• chr7-100024305-G-A
• rs148037051
• NM_003439.4:c.578G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003439.4(ZKSCAN1):​c.578G>A​(p.Arg193Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: ZKSCAN1 NM_003439.4 missense, splice_region
• Scores: Splicing: ADA: 0.0001079
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 9 publications found

Genes affected

ZKSCAN1 (HGNC:13101): (zinc finger with KRAB and SCAN domains 1) This gene encodes a member of the Kruppel C2H2-type zinc-finger family of proteins. This encoded protein may function as a transcription factor that regulates the expression of GABA type-A receptors in the brain. Transcripts from this gene have been shown to form stable and abundant circular RNAs. Elevated expression of this gene has been observed in gastric cancer and the encoded protein may stimulate migration and invasion of human gastric cancer cells. [provided by RefSeq, Oct 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023708314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZKSCAN1	NM_003439.4	c.578G>A	p.Arg193Gln	missense_variant, splice_region_variant	Exon 3 of 6	ENST00000324306.11	NP_003430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZKSCAN1	ENST00000324306.11	c.578G>A	p.Arg193Gln	missense_variant, splice_region_variant	Exon 3 of 6	1	NM_003439.4	ENSP00000323148.6

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152138 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 251052 AF XY: 0.0000737

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000404 AC: 59 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.0000330 AC XY: 24 AN XY: 727158

African (AFR) AF: 0.000777 AC: 26 AN: 33476

American (AMR) AF: 0.000224 AC: 10 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111958

Other (OTH) AF: 0.0000662 AC: 4 AN: 60394

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152256 Hom.: 0 Cov.: 31 AF XY: 0.000201 AC XY: 15 AN XY: 74462

African (AFR) AF: 0.000578 AC: 24 AN: 41538

American (AMR) AF: 0.000131 AC: 2 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000711 Hom.: 1

Bravo AF: 0.000170

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.578G>A (p.R193Q) alteration is located in exon 3 (coding exon 2) of the ZKSCAN1 gene. This alteration results from a G to A substitution at nucleotide position 578, causing the arginine (R) at amino acid position 193 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	0.10
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T;.;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.0045	T
MetaRNN	Benign	0.024	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L;.;.
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;N;.
REVEL	Benign	0.015
Sift	Benign	0.25	T;T;.
Sift4G	Benign	0.56	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.21
MVP		0.26
MPC		0.56
ClinPred		0.014	T
GERP RS		2.5
Varity_R		0.037
gMVP		0.17
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.0080
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: rs148037051; hg19: chr7-99621928; COSMIC: COSV60875289; COSMIC: COSV60875289;