chr2-112236575-C-A

Variant names:

• chr2-112236575-C-A
• rs76397380
• NM_032494.3:c.491G>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_032494.3(ZC3H8):​c.491G>T​(p.Gly164Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000692 in 1,613,470 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. G164D) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (1 hom.)
• Consequence: ZC3H8 NM_032494.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.389

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052863955).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZC3H8	NM_032494.3	c.491G>T	p.Gly164Val	missense_variant	Exon 4 of 9	ENST00000409573.7	NP_115883.2
ZC3H8	XR_001738994.2	n.552G>T		non_coding_transcript_exon_variant	Exon 4 of 9
FBLN7	XR_007069507.1	n.10509-2546C>A		intron_variant	Intron 8 of 9
FBLN7	XR_007069508.1	n.10508+5690C>A		intron_variant	Intron 8 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZC3H8	ENST00000409573.7	c.491G>T	p.Gly164Val	missense_variant	Exon 4 of 9	5	NM_032494.3	ENSP00000386488.1
ZC3H8	ENST00000466259.1	n.398G>T		non_coding_transcript_exon_variant	Exon 2 of 4	2
ZC3H8	ENST00000474234.5	n.671G>T		non_coding_transcript_exon_variant	Exon 5 of 7	5
ZC3H8	ENST00000464305.1	n.*11G>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 580 AN: 152184 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000845 AC: 210 AN: 248586 Hom.: 0 AF XY: 0.000556 AC XY: 75 AN XY: 134870

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000368 AC: 537 AN: 1461168 Hom.: 1 Cov.: 30 AF XY: 0.000297 AC XY: 216 AN XY: 726872

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.000606

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.000895

GnomAD4 genome AF: 0.00381 AC: 580 AN: 152302 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 251 AN XY: 74470

Gnomad4 AFR AF: 0.0134

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000138 Hom.: 0

Bravo AF: 0.00463

ExAC AF: 0.00111 AC: 134

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.075	T;T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.63	.;T;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N;N;.
REVEL	Benign	0.069
Sift	Benign	0.083	T;T;.
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.45	B;B;.
Vest4		0.13
MVP		0.13
MPC		0.20
ClinPred		0.013	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.34

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: rs76397380; hg19: chr2-112994152;