chr4-82426523-C-T

Variant names:

• chr4-82426523-C-T
• rs587777669
• NM_031372.4:c.1132G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM2 PM5 PP3 PP5_Very_Strong

The NM_031372.4(HNRNPDL):​c.1132G>A​(p.Asp378Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D378H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.81
• Publications: 10 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: Pathogenic. The variant received 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-82426523-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 144074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• PP5: Variant 4-82426523-C-T is Pathogenic according to our data. Variant chr4-82426523-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 144073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1132G>A	p.Asp378Asn	missense	Exon 6 of 8	NP_112740.1	O14979-1
	HNRNPDL	NM_001207000.1		c.1022-394G>A		intron	N/A	NP_001193929.1	A0A087WUK2
	HNRNPDL	NR_003249.2		n.1667G>A		non_coding_transcript_exon	Exon 6 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.1132G>A	p.Asp378Asn	missense	Exon 6 of 8	ENSP00000295470.5	O14979-1
	HNRNPDL	ENST00000621267.4	TSL:1	c.1132G>A	p.Asp378Asn	missense	Exon 6 of 8	ENSP00000483254.1	O14979-1
	HNRNPDL	ENST00000507721.5	TSL:1	c.775G>A	p.Asp259Asn	missense	Exon 6 of 7	ENSP00000480156.1	O14979-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Autosomal dominant limb-girdle muscular dystrophy type 1G (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.80
Sift	Benign	0.18	T
Sift4G	Benign	0.15	T
Polyphen		0.99	D
Vest4		0.70
MutPred		0.35		Gain of glycosylation at T380 (P = 0.0377)
MVP		0.87
MPC		0.53
ClinPred		0.89	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.84
Mutation Taster		=4/96	disease causing

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: rs587777669; hg19: chr4-83347676;