Genetic Variant ZFC3H1:p.Met1676Ile (chr12-71619947-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_144982.5(ZFC3H1):c.5028G>T(p.Met1676Ile) 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. 15/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ZFC3H1
NM_144982.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.396

Publications

1 publications found

Variant links:

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]

ZFC3H1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04275924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZFC3H1	NM_144982.5 link	c.5028G>T	p.Met1676Ile	missense_variant	Exon 26 of 35	ENST00000378743.9	NP_659419.3	O60293-1
ZFC3H1	XM_047428485.1 link	c.3849G>T	p.Met1283Ile	missense_variant	Exon 26 of 35		XP_047284441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZFC3H1	ENST00000378743.9 link	c.5028G>T	p.Met1676Ile	missense_variant	Exon 26 of 35	1	NM_144982.5	ENSP00000368017.4	O60293-1
ZFC3H1	ENST00000552994.5 link	n.5028G>T		non_coding_transcript_exon_variant	Exon 26 of 34	1		ENSP00000446995.1	O60293-2
ZFC3H1	ENST00000546771.1 link	n.19G>T		non_coding_transcript_exon_variant	Exon 1 of 3	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1439426

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712534

African (AFR)

AF:

0.00

AC:

AN:

32608

American (AMR)

AF:

0.00

AC:

AN:

41992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25586

East Asian (EAS)

AF:

0.00

AC:

AN:

39300

South Asian (SAS)

AF:

0.00

AC:

AN:

83148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099042

Other (OTH)

AF:

0.00

AC:

AN:

59400

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

5.9

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.027

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.20

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0059

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.40

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.11

REVEL

Benign

0.12

Sift

Benign

0.14

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.31

MutPred

0.28

Gain of catalytic residue at I1681 (P = 0.0469);

MVP

0.043

MPC

0.39

ClinPred

0.080

GERP RS

-0.75

Varity_R

0.034

gMVP

0.31

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over