12-71619960-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS2_Supporting

The NM_144982.5(ZFC3H1):ā€‹c.5015T>Cā€‹(p.Val1672Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,597,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000015 ( 0 hom. )

Consequence

ZFC3H1
NM_144982.5 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.83
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.28103966).
BS2
High AC in GnomAdExome4 at 21 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ZFC3H1NM_144982.5 linkuse as main transcriptc.5015T>C p.Val1672Ala missense_variant 26/35 ENST00000378743.9
ZFC3H1XM_047428485.1 linkuse as main transcriptc.3836T>C p.Val1279Ala missense_variant 26/35

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ZFC3H1ENST00000378743.9 linkuse as main transcriptc.5015T>C p.Val1672Ala missense_variant 26/351 NM_144982.5 P1O60293-1
ZFC3H1ENST00000552994.5 linkuse as main transcriptc.5015T>C p.Val1672Ala missense_variant, NMD_transcript_variant 26/341 O60293-2
ZFC3H1ENST00000546771.1 linkuse as main transcriptn.6T>C non_coding_transcript_exon_variant 1/33

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151996
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000411
AC:
1
AN:
243154
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
131760
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000899
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000145
AC:
21
AN:
1445554
Hom.:
0
Cov.:
30
AF XY:
0.0000126
AC XY:
9
AN XY:
716370
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000181
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151996
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74246
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 24, 2024The c.5015T>C (p.V1672A) alteration is located in exon 26 (coding exon 26) of the ZFC3H1 gene. This alteration results from a T to C substitution at nucleotide position 5015, causing the valine (V) at amino acid position 1672 to be replaced by an alanine (A). 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
Uncertain
0.48
BayesDel_addAF
Benign
-0.037
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.046
T
Eigen
Benign
0.10
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T
M_CAP
Benign
0.0071
T
MetaRNN
Benign
0.28
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.5
N
REVEL
Benign
0.14
Sift
Uncertain
0.0040
D
Sift4G
Uncertain
0.0020
D
Polyphen
0.089
B
Vest4
0.54
MutPred
0.31
Gain of catalytic residue at H1675 (P = 0.0235);
MVP
0.043
MPC
0.46
ClinPred
0.57
D
GERP RS
5.7
Varity_R
0.14
gMVP
0.43

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1187895618; hg19: chr12-72013740; API