6-28232802-T-C

Position:

• chr6-28232802-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006299.5(ZSCAN9):​c.809T>C​(p.Ile270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ZSCAN9 NM_006299.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.214

Genes affected

ZSCAN9 (HGNC:12984): (zinc finger and SCAN domain containing 9) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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=0.061614603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZSCAN9	NM_006299.5	c.809T>C	p.Ile270Thr	missense_variant	4/4	ENST00000252207.10	NP_006290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZSCAN9	ENST00000252207.10	c.809T>C	p.Ile270Thr	missense_variant	4/4	1	NM_006299.5	ENSP00000252207	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461890 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000765

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 Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2022

The c.962T>C (p.I321T) alteration is located in exon 5 (coding exon 4) of the ZSCAN9 gene. This alteration results from a T to C substitution at nucleotide position 962, causing the isoleucine (I) at amino acid position 321 to be replaced by a threonine (T). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.041	.;T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.22	T;.;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.062	T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.50	.;N;N;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N;N;N;D
REVEL	Benign	0.066
Sift	Uncertain	0.0020	D;T;T;D
Sift4G	Uncertain	0.036	D;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.036
MutPred		0.28		.;Loss of stability (P = 0.0229);Loss of stability (P = 0.0229);.;
MVP		0.055
MPC		0.15
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.076
gMVP		0.038

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

Other links and lift over

dbSNP: rs1760355558; hg19: chr6-28200580;