rs201774571

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_031372.4(HNRNPDL):c.248C>T(p.Pro83Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 1,610,042 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P83A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 2 hom. )

Consequence

HNRNPDL
NM_031372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.94

Variant links:

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]

HNRNPDL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.02641508).

BP6

Variant 4-82429443-G-A is Benign according to our data. Variant chr4-82429443-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 533022.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HNRNPDL	NM_031372.4 linkuse as main transcript	c.248C>T	p.Pro83Leu	missense_variant	1/8	ENST00000295470.10
HNRNPDL	NM_001207000.1 linkuse as main transcript	c.248C>T	p.Pro83Leu	missense_variant	1/7
HNRNPDL	NR_003249.2 linkuse as main transcript	n.783C>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10 linkuse as main transcript	c.248C>T	p.Pro83Leu	missense_variant	1/8	1	NM_031372.4	P4	O14979-1

Frequencies

GnomAD3 genomes

AF:

0.000514

AC:

AN:

151694

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000884

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000784

AC:

186

AN:

237318

Hom.:

AF XY:

0.000799

AC XY:

104

AN XY:

130142

show subpopulations

Gnomad AFR exome

AF:

0.000139

Gnomad AMR exome

AF:

0.000531

Gnomad ASJ exome

AF:

0.000817

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.0000474

Gnomad NFE exome

AF:

0.000996

Gnomad OTH exome

AF:

0.00327

GnomAD4 exome

AF:

0.000742

AC:

1082

AN:

1458230

Hom.:

Cov.:

AF XY:

0.000778

AC XY:

564

AN XY:

725278

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000587

Gnomad4 ASJ exome

AF:

0.000922

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00113

Gnomad4 FIN exome

AF:

0.0000764

Gnomad4 NFE exome

AF:

0.000752

Gnomad4 OTH exome

AF:

0.000830

GnomAD4 genome

AF:

0.000514

AC:

AN:

151812

Hom.:

Cov.:

AF XY:

0.000499

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000885

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000853

Hom.:

Bravo

AF:

0.000404

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000772

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.248C>T (p.P83L) alteration is located in exon 1 (coding exon 1) of the HNRNPDL gene. This alteration results from a C to T substitution at nucleotide position 248, causing the proline (P) at amino acid position 83 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Autosomal dominant limb-girdle muscular dystrophy type 1G

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.050

T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

.;D;D

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.026

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

0.98

D;D

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.89

N;.;.

REVEL

Benign

0.066

Sift

Pathogenic

0.0

D;.;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.010

B;B;.

Vest4

0.43

MVP

0.68

MPC

1.2

ClinPred

0.12

GERP RS

2.5

Varity_R

0.23

gMVP

0.21

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over