4-82427499-T-C

Position:

• chr4-82427499-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_031372.4(HNRNPDL):​c.840A>G​(p.Thr280=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0266 in 1,610,262 control chromosomes in the GnomAD database, including 639 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T280T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (53 hom., cov: 33)
  • Exomes 𝑓: 0.027 (586 hom.)
• Consequence: HNRNPDL NM_031372.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.489

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 4-82427499-T-C is Benign according to our data. Variant chr4-82427499-T-C is described in ClinVar as [Benign]. Clinvar id is 464392.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-82427499-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0214 (3264/152352) while in subpopulation NFE AF= 0.0323 (2195/68032). AF 95% confidence interval is 0.0311. There are 53 homozygotes in gnomad4. There are 1490 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3264 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.840A>G	p.Thr280=	synonymous_variant	4/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.840A>G	p.Thr280=	synonymous_variant	4/7
HNRNPDL	NR_003249.2	n.1375A>G		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.840A>G	p.Thr280=	synonymous_variant	4/8	1	NM_031372.4	P4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3264 AN: 152234 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.00794

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0323

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0213 AC: 5305 AN: 248940 Hom.: 84 AF XY: 0.0220 AC XY: 2953 AN XY: 134488

Gnomad AFR exome AF: 0.00706

Gnomad AMR exome AF: 0.0185

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00640

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.0342

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0271 AC: 39553 AN: 1457910 Hom.: 586 Cov.: 30 AF XY: 0.0268 AC XY: 19464 AN XY: 725204

Gnomad4 AFR exome AF: 0.00638

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.0146

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00655

Gnomad4 FIN exome AF: 0.00862

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0214 AC: 3264 AN: 152352 Hom.: 53 Cov.: 33 AF XY: 0.0200 AC XY: 1490 AN XY: 74490

Gnomad4 AFR AF: 0.00799

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.0323

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0274 Hom.: 37

Bravo AF: 0.0238

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0343

EpiControl AF: 0.0399

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs61729822; hg19: chr4-83348652;