rs760917145

chr4-82429438-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_031372.4(HNRNPDL):c.253C>T(p.Leu85Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,611,492 control chromosomes in the GnomAD database, including 1 homozygotes. 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. L85L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: HNRNPDL NM_031372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25942618).
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.253C>T	p.Leu85Phe	missense_variant	1/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.253C>T	p.Leu85Phe	missense_variant	1/7
HNRNPDL	NR_003249.2	n.788C>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.253C>T	p.Leu85Phe	missense_variant	1/8	1	NM_031372.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000417 AC: 10 AN: 239762 Hom.: 0 AF XY: 0.0000381 AC XY: 5 AN XY: 131310

Gnomad AFR exome AF: 0.0000681

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000130 AC: 19 AN: 1459444 Hom.: 1 Cov.: 33 AF XY: 0.0000152 AC XY: 11 AN XY: 725968

Gnomad4 AFR exome AF: 0.0000599

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74258

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.0000189

ExAC AF: 0.0000580 AC: 7

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

Oct 30, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 464385). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (Invitae). This variant is present in population databases (rs760917145, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 85 of the HNRNPDL protein (p.Leu85Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.29
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.031	T;T;T
Eigen	Benign	0.046
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.15	N;.;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.034	D;D;D
Polyphen		0.84	P;P;.
Vest4		0.34
MutPred		0.33		Loss of glycosylation at P83 (P = 0.0224);Loss of glycosylation at P83 (P = 0.0224);Loss of glycosylation at P83 (P = 0.0224);
MVP		0.53
MPC		1.1
ClinPred		0.20	T
GERP RS		4.0
Varity_R		0.42
gMVP		0.095

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: rs760917145; hg19: chr4-83350591;