rs749981753

Variant names:

• chr4-82429578-AGCTGCCGCGGCGGCC-A
• rs749981753
• NM_031372.4:c.98_112delGGCCGCCGCGGCAGC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM4 BP6_Moderate BS2

The NM_031372.4(HNRNPDL):​c.98_112delGGCCGCCGCGGCAGC​(p.Arg33_Gln37del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000267 in 1,389,774 control chromosomes in the GnomAD database, including 3 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. R33R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (2 hom.)
• Consequence: HNRNPDL NM_031372.4 disruptive_inframe_deletion
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.30
• 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):

• 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: Likely_benign. The variant received -4 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_031372.4.
• BP6: Variant 4-82429578-AGCTGCCGCGGCGGCC-A is Benign according to our data. Variant chr4-82429578-AGCTGCCGCGGCGGCC-A is described in ClinVar as Benign. ClinVar VariationId is 464395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 208 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	NM_031372.4	MANE Select	c.98_112delGGCCGCCGCGGCAGC	p.Arg33_Gln37del	disruptive_inframe_deletion	Exon 1 of 8	NP_112740.1	O14979-1
	HNRNPDL	NM_001207000.1		c.98_112delGGCCGCCGCGGCAGC	p.Arg33_Gln37del	disruptive_inframe_deletion	Exon 1 of 7	NP_001193929.1	A0A087WUK2
	HNRNPDL	NR_003249.2		n.633_647delGGCCGCCGCGGCAGC		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.98_112delGGCCGCCGCGGCAGC	p.Arg33_Gln37del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000295470.5	O14979-1
	HNRNPDL	ENST00000621267.4	TSL:1	c.98_112delGGCCGCCGCGGCAGC	p.Arg33_Gln37del	disruptive_inframe_deletion	Exon 1 of 8	ENSP00000483254.1	O14979-1
	HNRNPDL	ENST00000614627.4	TSL:1	c.98_112delGGCCGCCGCGGCAGC	p.Arg33_Gln37del	disruptive_inframe_deletion	Exon 1 of 7	ENSP00000478723.1	A0A087WUK2

Frequencies

GnomAD3 genomes AF: 0.00137 AC: 208 AN: 151346 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000949

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.000963

GnomAD2 exomes AF: 0.000363 AC: 7 AN: 19300 AF XY: 0.000405

Gnomad AFR exome AF: 0.00723

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 163 AN: 1238310 Hom.: 2 AF XY: 0.000116 AC XY: 70 AN XY: 601618

African (AFR) AF: 0.00573 AC: 136 AN: 23732

American (AMR) AF: 0.000272 AC: 3 AN: 11030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16982

East Asian (EAS) AF: 0.00 AC: 0 AN: 28488

South Asian (SAS) AF: 0.0000541 AC: 3 AN: 55416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3626

European-Non Finnish (NFE) AF: 0.0000139 AC: 14 AN: 1008374

Other (OTH) AF: 0.000138 AC: 7 AN: 50578

GnomAD4 genome AF: 0.00137 AC: 208 AN: 151464 Hom.: 1 Cov.: 32 AF XY: 0.00134 AC XY: 99 AN XY: 74036

African (AFR) AF: 0.00464 AC: 192 AN: 41360

American (AMR) AF: 0.000524 AC: 8 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4984

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.0000949 AC: 1 AN: 10542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000738 AC: 5 AN: 67748

Other (OTH) AF: 0.000953 AC: 2 AN: 2098

Alfa AF: 0.00114 Hom.: 0

Bravo AF: 0.00134

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=123/77	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs749981753; hg19: chr4-83350731;