chr4-82425953-T-C

Variant names:

• chr4-82425953-T-C
• rs10026631
• ENST00000507721.5:c.*106A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000507721.5(HNRNPDL):​c.*106A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 888,944 control chromosomes in the GnomAD database, including 633 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (84 hom., cov: 33)
  • Exomes 𝑓: 0.033 (549 hom.)
• Consequence: HNRNPDL ENST00000507721.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.494
• Publications: 2 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-82425953-T-C is Benign according to our data. Variant chr4-82425953-T-C is described in ClinVar as Benign. ClinVar VariationId is 1284243.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0268 (4074/152274) while in subpopulation NFE AF = 0.0395 (2685/67996). AF 95% confidence interval is 0.0382. There are 84 homozygotes in GnomAd4. There are 2010 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4074 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000507721.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	NM_031372.4	MANE Select	c.*22+84A>G		intron	N/A	NP_112740.1	O14979-1
	HNRNPDL	NM_001207000.1		c.*22+84A>G		intron	N/A	NP_001193929.1	A0A087WUK2
	HNRNPDL	NR_003249.2		n.1820+84A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	ENST00000507721.5	TSL:1	c.*106A>G		3_prime_UTR	Exon 7 of 7	ENSP00000480156.1	O14979-2
	HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.*22+84A>G		intron	N/A	ENSP00000295470.5	O14979-1
	HNRNPDL	ENST00000621267.4	TSL:1	c.*22+84A>G		intron	N/A	ENSP00000483254.1	O14979-1

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4075 AN: 152156 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00656

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.0133

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0672

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0395

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.0331 AC: 24361 AN: 736670 Hom.: 549 Cov.: 10 AF XY: 0.0325 AC XY: 12576 AN XY: 386838

African (AFR) AF: 0.00540 AC: 102 AN: 18872

American (AMR) AF: 0.0148 AC: 538 AN: 36466

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 359 AN: 20342

East Asian (EAS) AF: 0.0000849 AC: 3 AN: 35352

South Asian (SAS) AF: 0.00756 AC: 489 AN: 64644

European-Finnish (FIN) AF: 0.0624 AC: 3046 AN: 48828

Middle Eastern (MID) AF: 0.00549 AC: 15 AN: 2730

European-Non Finnish (NFE) AF: 0.0396 AC: 18746 AN: 473474

Other (OTH) AF: 0.0296 AC: 1063 AN: 35962

GnomAD4 genome AF: 0.0268 AC: 4074 AN: 152274 Hom.: 84 Cov.: 33 AF XY: 0.0270 AC XY: 2010 AN XY: 74454

African (AFR) AF: 0.00654 AC: 272 AN: 41564

American (AMR) AF: 0.0188 AC: 287 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0133 AC: 46 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4822

European-Finnish (FIN) AF: 0.0672 AC: 713 AN: 10604

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0395 AC: 2685 AN: 67996

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.0335 Hom.: 23

Bravo AF: 0.0220

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs10026631; hg19: chr4-83347106;