14-21231018-C-T

Variant names:

• chr14-21231018-C-T
• NM_004500.4:c.296G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.76

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]

ACMG classification

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
HNRNPC	NM_004500.4	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 9	ENST00000553300.6	NP_004491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPC	ENST00000553300.6	c.296G>A	p.Arg99Gln	missense_variant	Exon 4 of 9	1	NM_004500.4	ENSP00000450544.1

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

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;