12-71615236-T-A

Position:

• chr12-71615236-T-A

Variant summary

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

The NM_144982.5(ZFC3H1):​c.5225A>T​(p.His1742Leu) variant causes a missense 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. 15/21 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)
• Consequence: ZFC3H1 NM_144982.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.12

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=0.1463378).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZFC3H1	NM_144982.5	c.5225A>T	p.His1742Leu	missense_variant	28/35	ENST00000378743.9	NP_659419.3
ZFC3H1	XM_047428485.1	c.4046A>T	p.His1349Leu	missense_variant	28/35		XP_047284441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZFC3H1	ENST00000378743.9	c.5225A>T	p.His1742Leu	missense_variant	28/35	1	NM_144982.5	ENSP00000368017.4
ZFC3H1	ENST00000552994.5	n.5225A>T		non_coding_transcript_exon_variant	28/34	1		ENSP00000446995.1
ZFC3H1	ENST00000546771.1	n.216A>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Sep 04, 2024

The c.5225A>T (p.H1742L) alteration is located in exon 28 (coding exon 28) of the ZFC3H1 gene. This alteration results from a A to T substitution at nucleotide position 5225, causing the histidine (H) at amino acid position 1742 to be replaced by a leucine (L). 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	0.090
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.091
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.068
Sift	Benign	0.23	T
Sift4G	Uncertain	0.012	D
Polyphen		0.039	B
Vest4		0.29
MutPred		0.33		Gain of catalytic residue at Q1743 (P = 0.003);
MVP		0.043
MPC		0.44
ClinPred		0.58	D
GERP RS		5.0
Varity_R		0.14
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-72009016;