Genetic Variant NM_031372.4:c.1209T>C (chr4-82426113-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_031372.4(HNRNPDL):c.1209T>C(p.Tyr403Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,613,486 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 57 hom., cov: 33)

Exomes 𝑓: 0.027 ( 604 hom. )

Consequence

HNRNPDL
NM_031372.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.904

Publications

5 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):

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

HNRNPDL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 4-82426113-A-G is Benign according to our data. Variant chr4-82426113-A-G is described in ClinVar as Benign. ClinVar VariationId is 464381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0216 (3282/152294) while in subpopulation NFE AF = 0.0327 (2226/68018). AF 95% confidence interval is 0.0316. There are 57 homozygotes in GnomAd4. There are 1496 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 3282 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	UniProt
HNRNPDL	NM_031372.4	MANE Select	c.1209T>C	p.Tyr403Tyr	synonymous	Exon 7 of 8	NP_112740.1	O14979-1
HNRNPDL	NM_001207000.1		c.1038T>C	p.Tyr346Tyr	synonymous	Exon 6 of 7	NP_001193929.1	A0A087WUK2
HNRNPDL	NR_003249.2		n.1744T>C		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.1209T>C	p.Tyr403Tyr	synonymous	Exon 7 of 8	ENSP00000295470.5	O14979-1
HNRNPDL	ENST00000621267.4	TSL:1	c.1209T>C	p.Tyr403Tyr	synonymous	Exon 7 of 8	ENSP00000483254.1	O14979-1
HNRNPDL	ENST00000614627.4	TSL:1	c.1038T>C	p.Tyr346Tyr	synonymous	Exon 6 of 7	ENSP00000478723.1	A0A087WUK2

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3285

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00767

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00520

Gnomad FIN

AF:

0.00942

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0327

Gnomad OTH

AF:

0.0325

GnomAD2 exomes

AF:

0.0216

AC:

5443

AN:

251464

AF XY:

0.0222

show subpopulations

Gnomad AFR exome

AF:

0.00701

Gnomad AMR exome

AF:

0.0193

Gnomad ASJ exome

AF:

0.0143

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00813

Gnomad NFE exome

AF:

0.0347

Gnomad OTH exome

AF:

0.0316

GnomAD4 exome

AF:

0.0274

AC:

39975

AN:

1461192

Hom.:

604

Cov.:

AF XY:

0.0270

AC XY:

19632

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.00598

AC:

200

AN:

33470

American (AMR)

AF:

0.0207

AC:

927

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0147

AC:

383

AN:

26128

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39674

South Asian (SAS)

AF:

0.00670

AC:

578

AN:

86246

European-Finnish (FIN)

AF:

0.00863

AC:

461

AN:

53412

Middle Eastern (MID)

AF:

0.0330

AC:

190

AN:

5756

European-Non Finnish (NFE)

AF:

0.0321

AC:

35662

AN:

1111410

Other (OTH)

AF:

0.0260

AC:

1572

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

1743

3486

5230

6973

8716

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1272

2544

3816

5088

6360

<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:

0.0216

AC:

3282

AN:

152294

Hom.:

Cov.:

AF XY:

0.0201

AC XY:

1496

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00765

AC:

318

AN:

41584

American (AMR)

AF:

0.0309

AC:

472

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00499

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00942

AC:

100

AN:

10618

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0327

AC:

2226

AN:

68018

Other (OTH)

AF:

0.0322

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

166

332

498

664

830

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

114

152

190

<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:

0.0267

Hom.:

Bravo

AF:

0.0239

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0348

EpiControl

AF:

0.0401

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal dominant limb-girdle muscular dystrophy type 1G (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.0020

(source)

DANN

Benign

0.47

PhyloP100

-0.90

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Mutation Taster

=98/2

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over