2-112234235-T-A

Variant names:

• chr2-112234235-T-A
• rs199592500
• NM_032494.3:c.506A>T

Variant summary

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

The NM_032494.3(ZC3H8):​c.506A>T​(p.Asp169Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. D169G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ZC3H8 NM_032494.3 missense, splice_region
• Scores: Splicing: ADA: 0.00003525
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.605
• Publications: 1 publications found

Genes affected

ZC3H8 (HGNC:30941): (zinc finger CCCH-type containing 8) Enables RNA binding activity. Involved in several processes, including positive regulation of thymocyte apoptotic process; regulation of transcription, DNA-templated; and snRNA transcription. Located in Cajal body; histone locus body; and transcriptionally active chromatin. Part of transcription elongation factor complex. [provided by Alliance of Genome Resources, Apr 2022]

FBLN7 (HGNC:26740): (fibulin 7) Predicted to enable calcium ion binding activity; heparan sulfate proteoglycan binding activity; and heparin binding activity. Predicted to be involved in cell adhesion. Predicted to act upstream of or within positive regulation of biomineralization. Located in focal adhesion. [provided by Alliance of Genome Resources, Apr 2022]

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=0.083963186).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032494.3. 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
	ZC3H8	NM_032494.3	MANE Select	c.506A>T	p.Asp169Val	missense splice_region	Exon 5 of 9	NP_115883.2	Q8N5P1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZC3H8	ENST00000409573.7	TSL:5 MANE Select	c.506A>T	p.Asp169Val	missense splice_region	Exon 5 of 9	ENSP00000386488.1	Q8N5P1
	ZC3H8	ENST00000866700.1		c.506A>T	p.Asp169Val	missense splice_region	Exon 5 of 9	ENSP00000536759.1
	ZC3H8	ENST00000866701.1		c.506A>T	p.Asp169Val	missense splice_region	Exon 5 of 8	ENSP00000536760.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 223320 AF XY: 0.00000825

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000960

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436460 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 714092

African (AFR) AF: 0.00 AC: 0 AN: 32076

American (AMR) AF: 0.00 AC: 0 AN: 38754

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25576

East Asian (EAS) AF: 0.00 AC: 0 AN: 39340

South Asian (SAS) AF: 0.00 AC: 0 AN: 80710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.08e-7 AC: 1 AN: 1101878

Other (OTH) AF: 0.00 AC: 0 AN: 59508

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.60
PrimateAI	Benign	0.25	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.079
Sift	Uncertain	0.017	D
Sift4G	Benign	0.089	T
Polyphen		0.16	B
Vest4		0.14
MutPred		0.16		Gain of methylation at K171 (P = 0.0502)
MVP		0.13
MPC		0.25
ClinPred		0.16	T
GERP RS		-0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.43
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000035
dbscSNV1_RF	Benign	0.0040
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: rs199592500; hg19: chr2-112991812;