NM_031372.4:c.113T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_031372.4(HNRNPDL):c.113T>C(p.Leu38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00106 in 1,389,752 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. L38R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 1 hom. )

Consequence

HNRNPDL
NM_031372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 2.48

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant limb-girdle muscular dystrophy type 1G
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
muscular dystrophy, limb-girdle, autosomal dominant
Inheritance: AD Classification: MODERATE Submitted by: ClinGen

HNRNPDL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07384926).

BP6

Variant 4-82429578-A-G is Benign according to our data. Variant chr4-82429578-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464379.

BS2

High AC in GnomAd4 at 95 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031372.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNRNPDL	NM_031372.4	MANE Select	c.113T>C	p.Leu38Pro	missense	Exon 1 of 8	NP_112740.1
HNRNPDL	NM_001207000.1		c.113T>C	p.Leu38Pro	missense	Exon 1 of 7	NP_001193929.1
HNRNPDL	NR_003249.2		n.648T>C		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.113T>C	p.Leu38Pro	missense	Exon 1 of 8	ENSP00000295470.5
HNRNPDL	ENST00000621267.4	TSL:1	c.113T>C	p.Leu38Pro	missense	Exon 1 of 8	ENSP00000483254.1
HNRNPDL	ENST00000614627.4	TSL:1	c.113T>C	p.Leu38Pro	missense	Exon 1 of 7	ENSP00000478723.1

Frequencies

GnomAD3 genomes

AF:

0.000628

AC:

AN:

151344

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000412

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00108

Gnomad OTH

AF:

0.000482

GnomAD2 exomes

AF:

0.000311

AC:

AN:

19300

AF XY:

0.000405

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000765

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000654

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00111

AC:

1375

AN:

1238290

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

645

AN XY:

601606

show subpopulations

African (AFR)

AF:

0.000295

AC:

AN:

23730

American (AMR)

AF:

0.000272

AC:

AN:

11030

Ashkenazi Jewish (ASJ)

AF:

0.000177

AC:

AN:

16982

East Asian (EAS)

AF:

0.000211

AC:

AN:

28488

South Asian (SAS)

AF:

0.000144

AC:

AN:

55416

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3626

European-Non Finnish (NFE)

AF:

0.00130

AC:

1309

AN:

1008356

Other (OTH)

AF:

0.000771

AC:

AN:

50578

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.422

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

180

240

300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000627

AC:

AN:

151462

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

AN XY:

74034

show subpopulations

African (AFR)

AF:

0.000411

AC:

AN:

41360

American (AMR)

AF:

0.000196

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

4984

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10542

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00108

AC:

AN:

67746

Other (OTH)

AF:

0.000477

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000265

Hom.:

Bravo

AF:

0.000586

ExAC

AF:

0.0000455

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1G

Benign:2

Dec 13, 2024

Revvity Omics, Revvity

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.113T>C (p.L38P) alteration is located in exon 1 (coding exon 1) of the HNRNPDL gene. This alteration results from a T to C substitution at nucleotide position 113, causing the leucine (L) at amino acid position 38 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.019

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.69

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

2.5

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.15

REVEL

Benign

0.16

Sift

Pathogenic

0.0

Polyphen

0.0010

Vest4

0.41

MVP

0.62

MPC

1.6

ClinPred

0.29

GERP RS

4.1

PromoterAI

0.030

Neutral

(source)

Varity_R

0.41

gMVP

0.24

Mutation Taster

=74/26

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over