14-21231018-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_004500.4(HNRNPC):​c.296G>A​(p.Arg99Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HNRNPC
NM_004500.4 missense

Scores

4
7
8

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.76
Variant links:
Genes affected
HNRNPC (HGNC:5035): (heterogeneous nuclear ribonucleoprotein C) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins and they complex with heterogeneous nuclear RNA (hnRNA). These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some seem to shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene can act as a tetramer and is involved in the assembly of 40S hnRNP particles. Multiple transcript variants encoding at least two different isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-21231018-C-T is Pathogenic according to our data. Variant chr14-21231018-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3766075.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNRNPCNM_004500.4 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 9 ENST00000553300.6 NP_004491.2 P07910-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNRNPCENST00000553300.6 linkc.296G>A p.Arg99Gln missense_variant Exon 4 of 9 1 NM_004500.4 ENSP00000450544.1 P07910-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

not provided Pathogenic:1
Aug 28, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 37541189) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.11
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.11
T;.;T;D;.;.;T;.;T;.;T;D;.;.;D;T;.;T;.;T;.;.
Eigen
Uncertain
0.64
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.78
.;.;.;.;T;.;T;T;T;T;T;.;.;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.54
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.80
T
MutationAssessor
Benign
1.8
.;L;.;L;.;L;.;.;.;L;.;L;L;L;L;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-2.9
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N
REVEL
Benign
0.26
Sift
Uncertain
0.0020
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;.;.
Polyphen
0.88
P;P;.;P;.;P;P;D;.;D;.;P;P;P;P;.;.;.;.;.;.;.
Vest4
0.69
MutPred
0.50
Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);.;Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);Loss of MoRF binding (P = 0.0199);
MVP
0.68
ClinPred
0.96
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.59
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: chr14-21699177; API