4-82426064-A-G

Variant names:

• chr4-82426064-A-G
• NM_031372.4:c.1258T>C

Variant summary

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

The NM_031372.4(HNRNPDL):​c.1258T>C​(p.Tyr420His) 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: 33)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.1258T>C	p.Tyr420His	missense_variant	Exon 7 of 8	ENST00000295470.10	NP_112740.1
HNRNPDL	NM_001207000.1	c.1087T>C	p.Tyr363His	missense_variant	Exon 6 of 7		NP_001193929.1
HNRNPDL	NR_003249.2	n.1793T>C		non_coding_transcript_exon_variant	Exon 7 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.1258T>C	p.Tyr420His	missense_variant	Exon 7 of 8	1	NM_031372.4	ENSP00000295470.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;.;.;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.8	N;.;.;.;.;.
REVEL	Uncertain	0.46
Sift	Pathogenic	0.0	D;.;.;.;.;.
Sift4G	Uncertain	0.023	D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.76
MutPred		0.30		Gain of glycosylation at Y417 (P = 0.0207);Gain of glycosylation at Y417 (P = 0.0207);.;.;.;.;
MVP		0.74
MPC		0.70
ClinPred		0.96	D
GERP RS		5.8
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.51
gMVP		0.88

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: chr4-83347217;