rs911762606

chr4-82429581-T-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_031372.4(HNRNPDL):c.110A>C(p.Gln37Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,383,816 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.966

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14141434).
• BP6: Variant 4-82429581-T-G is Benign according to our data. Variant chr4-82429581-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 93 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.110A>C	p.Gln37Pro	missense_variant	1/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.110A>C	p.Gln37Pro	missense_variant	1/7
HNRNPDL	NR_003249.2	n.645A>C		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.110A>C	p.Gln37Pro	missense_variant	1/8	1	NM_031372.4	P4

Frequencies

GnomAD3 genomes AF: 0.000617 AC: 93 AN: 150670 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000343

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.000306 AC: 5 AN: 16354 Hom.: 0 AF XY: 0.000480 AC XY: 4 AN XY: 8336

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00108 AC: 1336 AN: 1233046 Hom.: 1 Cov.: 32 AF XY: 0.00104 AC XY: 625 AN XY: 598706

Gnomad4 AFR exome AF: 0.000257

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.000178

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00127

Gnomad4 OTH exome AF: 0.000754

GnomAD4 genome AF: 0.000617 AC: 93 AN: 150770 Hom.: 0 Cov.: 32 AF XY: 0.000421 AC XY: 31 AN XY: 73648

Gnomad4 AFR AF: 0.000342

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000857 Hom.: 0

ExAC AF: 0.0000502 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2022	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2021

The c.110A>C (p.Q37P) alteration is located in exon 1 (coding exon 1) of the HNRNPDL gene. This alteration results from a A to C substitution at nucleotide position 110, causing the glutamine (Q) at amino acid position 37 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Benign	0.97
DEOGEN2	Benign	0.018	T;T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.81	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.85	N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.060	N;.;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.;.
Polyphen		0.0040	B;B;.
Vest4		0.39
MVP		0.70
MPC		0.93
ClinPred		0.36	T
GERP RS		1.7
Varity_R		0.34
gMVP		0.21

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: rs911762606; hg19: chr4-83350734;