4-82427465-C-T

Position:

• chr4-82427465-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_031372.4(HNRNPDL):​c.874G>A​(p.Glu292Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 7.55

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.874G>A	p.Glu292Lys	missense_variant	4/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.874G>A	p.Glu292Lys	missense_variant	4/7
HNRNPDL	NR_003249.2	n.1409G>A		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.874G>A	p.Glu292Lys	missense_variant	4/8	1	NM_031372.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 20, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 533023). This variant has not been reported in the literature in individuals affected with HNRNPDL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 292 of the HNRNPDL protein (p.Glu292Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	.;D;D;.;.;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Benign	1.3	L;L;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;.;.;.;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.12	T;.;.;.;.;.
Sift4G	Benign	0.16	T;T;T;T;T;T
Polyphen		0.41	B;B;.;.;.;.
Vest4		0.78
MutPred		0.42		Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);Gain of MoRF binding (P = 0.0067);.;.;.;
MVP		0.92
MPC		1.5
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.47

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: rs1553900899; hg19: chr4-83348618;