rs1269836189

chr4-82429681-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/21 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2205413).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.10C>T	p.Pro4Ser	missense_variant	1/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.10C>T	p.Pro4Ser	missense_variant	1/7
HNRNPDL	NR_003249.2	n.545C>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.10C>T	p.Pro4Ser	missense_variant	1/8	1	NM_031372.4	P4

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000102

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant limb-girdle muscular dystrophy type 1G Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2017

This variant has not been reported in the literature in individuals with HNRNPDL-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces proline with serine at codon 4 of the HNRNPDL protein (p.Pro4Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;T;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.82	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.78	N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.15	N;.;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;.;.
Polyphen		0.0	B;B;.
Vest4		0.45
MutPred		0.20		Loss of catalytic residue at P4 (P = 0.0084);Loss of catalytic residue at P4 (P = 0.0084);Loss of catalytic residue at P4 (P = 0.0084);
MVP		0.45
MPC		1.1
ClinPred		0.56	D
GERP RS		3.5
Varity_R		0.21
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1269836189; hg19: chr4-83350834; COSMIC: COSV55022512; COSMIC: COSV55022512;