4-82426498-T-C

Variant names:

• chr4-82426498-T-C
• rs1721414403
• NM_031372.4:c.1157A>G

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, multiple submitters, no conflicts U:2
• 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 rank	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.1157A>G	p.Asn386Ser	missense_variant	Exon 6 of 8	ENST00000295470.10	NP_112740.1
HNRNPDL	NM_001207000.1	c.1022-369A>G		intron_variant	Intron 5 of 6		NP_001193929.1
HNRNPDL	NR_003249.2	n.1692A>G		non_coding_transcript_exon_variant	Exon 6 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.1157A>G	p.Asn386Ser	missense_variant	Exon 6 of 8	1	NM_031372.4	ENSP00000295470.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1G Uncertain:1

Sep 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 386 of the HNRNPDL protein (p.Asn386Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with HNRNPDL-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Oct 12, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.;.;.
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;