12-71627753-C-G

Position:

• chr12-71627753-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144982.5(ZFC3H1):​c.4128G>C​(p.Glu1376Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 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: not found (cov: 33)
• Consequence: ZFC3H1 NM_144982.5 missense, splice_region
• Scores: Splicing: ADA: 0.00003107
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.344

Genes affected

ZFC3H1 (HGNC:28328): (zinc finger C3H1-type containing) Predicted to enable metal ion binding activity. Predicted to be involved in RNA processing. Located in nucleus. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08738485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZFC3H1	NM_144982.5	c.4128G>C	p.Glu1376Asp	missense_variant, splice_region_variant	21/35	ENST00000378743.9
ZFC3H1	XM_047428485.1	c.2949G>C	p.Glu983Asp	missense_variant, splice_region_variant	21/35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZFC3H1	ENST00000378743.9	c.4128G>C	p.Glu1376Asp	missense_variant, splice_region_variant	21/35	1	NM_144982.5	P1
ZFC3H1	ENST00000552994.5	c.4128G>C	p.Glu1376Asp	missense_variant, splice_region_variant, NMD_transcript_variant	21/34	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

May 07, 2024

The c.4128G>C (p.E1376D) alteration is located in exon 21 (coding exon 21) of the ZFC3H1 gene. This alteration results from a G to C substitution at nucleotide position 4128, causing the glutamic acid (E) at amino acid position 1376 to be replaced by an aspartic acid (D). 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	0.075
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.072
Sift	Benign	0.12	T
Sift4G	Uncertain	0.047	D
Polyphen		0.63	P
Vest4		0.22
MutPred		0.21		Gain of catalytic residue at N1375 (P = 0.0532);
MVP		0.043
MPC		0.33
ClinPred		0.44	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.081
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000031
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-72021533;