rs1269836189

Variant names:

• chr4-82429681-G-A
• rs1269836189
• NM_031372.4:c.10C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-82429681-G-A
• chr4-82429681-G-C

Variant summary

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

The NM_031372.4(HNRNPDL):​c.10C>T​(p.Pro4Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000831 in 1,203,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• 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=0.2205413).

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.10C>T	p.Pro4Ser	missense	Exon 1 of 8	NP_112740.1
	HNRNPDL	NM_001207000.1		c.10C>T	p.Pro4Ser	missense	Exon 1 of 7	NP_001193929.1
	HNRNPDL	NR_003249.2		n.545C>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.10C>T	p.Pro4Ser	missense	Exon 1 of 8	ENSP00000295470.5
	HNRNPDL	ENST00000621267.4	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 8	ENSP00000483254.1
	HNRNPDL	ENST00000614627.4	TSL:1	c.10C>T	p.Pro4Ser	missense	Exon 1 of 7	ENSP00000478723.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.31e-7 AC: 1 AN: 1203838 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 579732

African (AFR) AF: 0.00 AC: 0 AN: 23550

American (AMR) AF: 0.000102 AC: 1 AN: 9826

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16348

East Asian (EAS) AF: 0.00 AC: 0 AN: 27774

South Asian (SAS) AF: 0.00 AC: 0 AN: 48256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3684

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 987640

Other (OTH) AF: 0.00 AC: 0 AN: 49342

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.13
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.3
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.45
MutPred		0.20		Loss of catalytic residue at P4 (P = 0.0084)
MVP		0.45
MPC		1.1
ClinPred		0.56	D
GERP RS		3.5
PromoterAI		-0.036	Neutral
Varity_R		0.21
gMVP		0.18
Mutation Taster		=88/12	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: rs1269836189; hg19: chr4-83350834; COSMIC: COSV55022512; COSMIC: COSV55022512;