14-21234081-G-A

Position:

• chr14-21234081-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BS2

The NM_004500.4(HNRNPC):​c.113C>T​(p.Ser38Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: HNRNPC NM_004500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPC	NM_004500.4	c.113C>T	p.Ser38Leu	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.113C>T	p.Ser38Leu	missense_variant	3/9	1	NM_004500.4	ENSP00000450544	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461682 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727148

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2024

The c.113C>T (p.S38L) alteration is located in exon 3 (coding exon 1) of the HNRNPC gene. This alteration results from a C to T substitution at nucleotide position 113, causing the serine (S) at amino acid position 38 to be replaced by a leucine (L). 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	0.55
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T;.;T;T;.;.;T;.;T;.;.;T;T;.;.;T;.;T;.;T;.;.;.;T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;.;.;.;D;.;D;D;D;T;D;D;.;.;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.58	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.6	.;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;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.9	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	0.27
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;T
Sift4G	Uncertain	0.049	D;T;T;T;T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;.
Polyphen		0.43	B;B;.;P;.;B;B;B;.;B;B;.;P;B;B;P;.;.;.;.;.;.;.;.
Vest4		0.44
MutPred		0.53		Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);Loss of methylation at K42 (P = 0.0516);
MVP		0.52
ClinPred		0.97	D
GERP RS		5.2
Varity_R		0.42
gMVP		0.89

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

Other links and lift over

dbSNP: rs1894400790; hg19: chr14-21702240; COSMIC: COSV60143700; COSMIC: COSV60143700;