4-82426498-T-C

Position:

• chr4-82426498-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_031372.4(HNRNPDL):​c.1157A>G​(p.Asn386Ser) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.74

Genes affected

HNRNPDL (HGNC:5037): (heterogeneous nuclear ribonucleoprotein D like) 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 has two RRM domains that bind to RNAs. Three alternatively spliced transcript variants have been described for this gene. One of the variants is probably not translated because the transcript is a candidate for nonsense-mediated mRNA decay. The protein isoforms encoded by this gene are similar to its family member HNRPD. [provided by RefSeq, May 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1338686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.1157A>G	p.Asn386Ser	missense_variant	6/8	ENST00000295470.10	NP_112740.1
HNRNPDL	NM_001207000.1	c.1022-369A>G		intron_variant			NP_001193929.1
HNRNPDL	NR_003249.2	n.1692A>G		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.1157A>G	p.Asn386Ser	missense_variant	6/8	1	NM_031372.4	ENSP00000295470	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

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

Oct 12, 2023

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.035	T;T;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.83	.;T;.;.;T
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.13	T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L;L;.;.;.
MutationTaster	Benign	0.70	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.010	N;.;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.13	T;.;.;.;.
Sift4G	Benign	0.50	T;T;T;T;T
Polyphen		0.0	B;B;.;.;.
Vest4		0.22
MutPred		0.36		Loss of stability (P = 0.1145);Loss of stability (P = 0.1145);.;.;.;
MVP		0.78
MPC		0.44
ClinPred		0.10	T
GERP RS		3.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.072
gMVP		0.71

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: rs1721414403; hg19: chr4-83347651;