4-82426519-T-G

Variant names:

• chr4-82426519-T-G
• rs749371373
• NM_031372.4:c.1136A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_031372.4(HNRNPDL):​c.1136A>C​(p.Tyr379Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y379C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.66
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.1136A>C	p.Tyr379Ser	missense_variant	Exon 6 of 8	ENST00000295470.10	NP_112740.1
HNRNPDL	NR_003249.2	n.1671A>C		non_coding_transcript_exon_variant	Exon 6 of 9
HNRNPDL	NM_001207000.1	c.1022-390A>C		intron_variant	Intron 5 of 6		NP_001193929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.1136A>C	p.Tyr379Ser	missense_variant	Exon 6 of 8	1	NM_031372.4	ENSP00000295470.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;T;.;.;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	.;D;.;.;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	3.0	M;M;.;.;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.8	D;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0070	D;.;.;.;.
Sift4G	Benign	0.078	T;T;D;D;D
Polyphen		1.0	D;D;.;.;.
Vest4		0.83
MutPred		0.43		Gain of glycosylation at T380 (P = 0.0377);Gain of glycosylation at T380 (P = 0.0377);.;.;.;
MVP		0.90
MPC		1.7
ClinPred		0.97	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.90
Mutation Taster		=26/74	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: rs749371373; hg19: chr4-83347672;