chr4-82426113-A-G

Position:

• chr4-82426113-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_031372.4(HNRNPDL):​c.1209T>C​(p.Tyr403=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0268 in 1,613,486 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (57 hom., cov: 33)
  • Exomes 𝑓: 0.027 (604 hom.)
• Consequence: HNRNPDL NM_031372.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.904

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 4-82426113-A-G is Benign according to our data. Variant chr4-82426113-A-G is described in ClinVar as [Benign]. Clinvar id is 464381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-82426113-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0216 (3282/152294) while in subpopulation NFE AF= 0.0327 (2226/68018). AF 95% confidence interval is 0.0316. There are 57 homozygotes in gnomad4. There are 1496 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3282 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPDL	NM_031372.4	c.1209T>C	p.Tyr403=	synonymous_variant	7/8	ENST00000295470.10
HNRNPDL	NM_001207000.1	c.1038T>C	p.Tyr346=	synonymous_variant	6/7
HNRNPDL	NR_003249.2	n.1744T>C		non_coding_transcript_exon_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.1209T>C	p.Tyr403=	synonymous_variant	7/8	1	NM_031372.4	P4

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3285 AN: 152176 Hom.: 57 Cov.: 33

Gnomad AFR AF: 0.00767

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0310

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00520

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0327

Gnomad OTH AF: 0.0325

GnomAD3 exomes AF: 0.0216 AC: 5443 AN: 251464 Hom.: 90 AF XY: 0.0222 AC XY: 3011 AN XY: 135910

Gnomad AFR exome AF: 0.00701

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00657

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0316

GnomAD4 exome AF: 0.0274 AC: 39975 AN: 1461192 Hom.: 604 Cov.: 30 AF XY: 0.0270 AC XY: 19632 AN XY: 726912

Gnomad4 AFR exome AF: 0.00598

Gnomad4 AMR exome AF: 0.0207

Gnomad4 ASJ exome AF: 0.0147

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00670

Gnomad4 FIN exome AF: 0.00863

Gnomad4 NFE exome AF: 0.0321

Gnomad4 OTH exome AF: 0.0260

GnomAD4 genome AF: 0.0216 AC: 3282 AN: 152294 Hom.: 57 Cov.: 33 AF XY: 0.0201 AC XY: 1496 AN XY: 74456

Gnomad4 AFR AF: 0.00765

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00942

Gnomad4 NFE AF: 0.0327

Gnomad4 OTH AF: 0.0322

Alfa AF: 0.0267 Hom.: 34

Bravo AF: 0.0239

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0348

EpiControl AF: 0.0401

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0020
DANN	Benign	0.47
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8

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: rs79373393; hg19: chr4-83347266;