14-21231020-T-A

Position:

• chr14-21231020-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004500.4(HNRNPC):​c.294A>T​(p.Lys98Asn) 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPC NM_004500.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.22

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33522207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPC	NM_004500.4	c.294A>T	p.Lys98Asn	missense_variant	4/9	ENST00000553300.6	NP_004491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPC	ENST00000553300.6	c.294A>T	p.Lys98Asn	missense_variant	4/9	1	NM_004500.4	ENSP00000450544	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

HNRNPC-related condition Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2024

The HNRNPC c.294A>T variant is predicted to result in the amino acid substitution p.Lys98Asn. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. An adjacent missense variant (p.Arg99Gln) was reported to be de novo in an individual with dysmorphic features, mild intellectual disability, and developmental delay (Niggl et al. 2023. PubMed ID: 37541189, See Table S4). Although we suspect that the c.294A>T (p.Lys98Asn) variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;T;D;.;.;T;.;T;.;T;D;.;.;D;T;.;T;.;T;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.82	.;.;.;.;T;.;T;T;T;T;T;.;.;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;M;.;M;.;M;.;.;.;M;.;M;M;M;M;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.019	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;T;.;.
Polyphen		0.57	P;B;.;B;.;B;P;P;.;B;.;B;B;B;B;.;.;.;.;.;.;.
Vest4		0.50
MutPred		0.46		Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);.;Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);Loss of methylation at K98 (P = 0.0033);
MVP		0.66
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.58
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr14-21699179;