rs527520007

Variant names:

• chr4-82427311-AC-A
• rs527520007
• NM_031372.4:c.907-8delG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_031372.4(HNRNPDL):​c.907-8delG variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,568,724 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: HNRNPDL NM_031372.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.464
• Publications: 0 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):

• 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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 4-82427311-AC-A is Benign according to our data. Variant chr4-82427311-AC-A is described in ClinVar as Benign. ClinVar VariationId is 464393.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 422 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	NM_031372.4	MANE Select	c.907-8delG		splice_region intron	N/A	NP_112740.1
	HNRNPDL	NM_001207000.1		c.907-8delG		splice_region intron	N/A	NP_001193929.1
	HNRNPDL	NR_003249.2		n.1442-8delG		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.907-8delG		splice_region intron	N/A	ENSP00000295470.5
	HNRNPDL	ENST00000621267.4	TSL:1	c.907-8delG		splice_region intron	N/A	ENSP00000483254.1
	HNRNPDL	ENST00000614627.4	TSL:1	c.907-8delG		splice_region intron	N/A	ENSP00000478723.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 416 AN: 152210 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00943

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000580 AC: 129 AN: 222602 AF XY: 0.000331

Gnomad AFR exome AF: 0.00780

Gnomad AMR exome AF: 0.0000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.000371

GnomAD4 exome AF: 0.000229 AC: 325 AN: 1416396 Hom.: 0 Cov.: 27 AF XY: 0.000192 AC XY: 135 AN XY: 704100

African (AFR) AF: 0.00819 AC: 254 AN: 31032

American (AMR) AF: 0.000118 AC: 4 AN: 33804

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39286

South Asian (SAS) AF: 0.0000507 AC: 4 AN: 78930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53208

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5636

European-Non Finnish (NFE) AF: 0.00000825 AC: 9 AN: 1091108

Other (OTH) AF: 0.000819 AC: 48 AN: 58632

GnomAD4 genome AF: 0.00277 AC: 422 AN: 152328 Hom.: 1 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74494

African (AFR) AF: 0.00941 AC: 391 AN: 41564

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.000218 Hom.: 0

Bravo AF: 0.00280

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant limb-girdle muscular dystrophy type 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.46
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: rs527520007; hg19: chr4-83348464;