14-21234174-T-C

Position:

• chr14-21234174-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000553300.6(HNRNPC):​c.20A>G​(p.Asn7Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNRNPC ENST00000553300.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.00

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPC	NM_004500.4	c.20A>G	p.Asn7Ser	missense_variant	3/9	ENST00000553300.6	NP_004491.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPC	ENST00000553300.6	c.20A>G	p.Asn7Ser	missense_variant	3/9	1	NM_004500.4	ENSP00000450544	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;.;T;D;.;.;T;.;T;.;.;T;D;.;.;D;.;T;.;T;.;.;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;.;.;.;D;.;D;D;D;D;D;D;.;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	2.0	.;M;.;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	Uncertain	0.77	T
PROVEAN	Uncertain	-4.2	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.054	T;D;T;T;D;D;T;T;T;D;T;T;T;D;D;T;T;T;T;T;D;T;T;T
Sift4G	Uncertain	0.036	D;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;P;.;.;.;.;.;.;.;.
Vest4		0.80
MutPred		0.38		Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);Gain of phosphorylation at N7 (P = 0.0546);
MVP		0.53
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-21702333;