rs1362920184

Variant names:

• chr4-82429656-G-A
• rs1362920184
• NM_031372.4:c.35C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-82429656-G-A
• chr4-82429656-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000295470.10(HNRNPDL):​c.35C>T​(p.Pro12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,214,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P12P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: HNRNPDL ENST00000295470.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.06
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23809832).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000295470.10. 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.35C>T	p.Pro12Leu	missense	Exon 1 of 8	NP_112740.1
	HNRNPDL	NM_001207000.1		c.35C>T	p.Pro12Leu	missense	Exon 1 of 7	NP_001193929.1
	HNRNPDL	NR_003249.2		n.570C>T		non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNRNPDL	ENST00000295470.10	TSL:1 MANE Select	c.35C>T	p.Pro12Leu	missense	Exon 1 of 8	ENSP00000295470.5
	HNRNPDL	ENST00000621267.4	TSL:1	c.35C>T	p.Pro12Leu	missense	Exon 1 of 8	ENSP00000483254.1
	HNRNPDL	ENST00000614627.4	TSL:1	c.35C>T	p.Pro12Leu	missense	Exon 1 of 7	ENSP00000478723.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000165 AC: 2 AN: 1214454 Hom.: 0 Cov.: 33 AF XY: 0.00000170 AC XY: 1 AN XY: 586524

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23614

American (AMR) AF: 0.00 AC: 0 AN: 9978

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16438

East Asian (EAS) AF: 0.00 AC: 0 AN: 27972

South Asian (SAS) AF: 0.00 AC: 0 AN: 50948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3706

European-Non Finnish (NFE) AF: 0.00000201 AC: 2 AN: 992938

Other (OTH) AF: 0.00 AC: 0 AN: 49652

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Polyphen		0.61	P
Vest4		0.39
MutPred		0.12		Loss of glycosylation at P16 (P = 0.0242)
MVP		0.72
MPC		1.2
ClinPred		0.66	D
GERP RS		2.5
PromoterAI		-0.35	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.21
gMVP		0.21
Mutation Taster		=84/16	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: rs1362920184; hg19: chr4-83350809;