rs61737724

Positions:

• chr4-82429610-G-A

Variant summary

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

The ENST00000295470.10(HNRNPDL):​c.81C>T​(p.Leu27=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,379,782 control chromosomes in the GnomAD database, including 552 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (55 hom., cov: 32)
  • Exomes 𝑓: 0.028 (497 hom.)
• Consequence: HNRNPDL ENST00000295470.10 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.234

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=-0.51).
• BP6: Variant 4-82429610-G-A is Benign according to our data. Variant chr4-82429610-G-A is described in ClinVar as [Benign]. Clinvar id is 464391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-82429610-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.234 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0208 (3151/151632) while in subpopulation NFE AF= 0.0322 (2179/67768). AF 95% confidence interval is 0.031. There are 55 homozygotes in gnomad4. There are 1441 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.81C>T	p.Leu27=	synonymous_variant	1/8	ENST00000295470.10	NP_112740.1
HNRNPDL	NM_001207000.1	c.81C>T	p.Leu27=	synonymous_variant	1/7		NP_001193929.1
HNRNPDL	NR_003249.2	n.616C>T		non_coding_transcript_exon_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.81C>T	p.Leu27=	synonymous_variant	1/8	1	NM_031372.4	ENSP00000295470	P4

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3154 AN: 151518 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.00591

Gnomad AMI AF: 0.00331

Gnomad AMR AF: 0.0304

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00519

Gnomad FIN AF: 0.00946

Gnomad MID AF: 0.0581

Gnomad NFE AF: 0.0322

Gnomad OTH AF: 0.0322

GnomAD3 exomes AF: 0.0217 AC: 389 AN: 17890 Hom.: 6 AF XY: 0.0201 AC XY: 175 AN XY: 8700

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.0267

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00755

Gnomad FIN exome AF: 0.00587

Gnomad NFE exome AF: 0.0412

Gnomad OTH exome AF: 0.0392

GnomAD4 exome AF: 0.0279 AC: 34307 AN: 1228150 Hom.: 497 Cov.: 33 AF XY: 0.0276 AC XY: 16407 AN XY: 595196

Gnomad4 AFR exome AF: 0.00407

Gnomad4 AMR exome AF: 0.0260

Gnomad4 ASJ exome AF: 0.0144

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00661

Gnomad4 FIN exome AF: 0.00828

Gnomad4 NFE exome AF: 0.0316

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0208 AC: 3151 AN: 151632 Hom.: 55 Cov.: 32 AF XY: 0.0194 AC XY: 1441 AN XY: 74114

Gnomad4 AFR AF: 0.00589

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00499

Gnomad4 FIN AF: 0.00946

Gnomad4 NFE AF: 0.0322

Gnomad4 OTH AF: 0.0318

Alfa AF: 0.0220 Hom.: 7

Bravo AF: 0.0231

Asia WGS AF: 0.00433 AC: 15 AN: 3478

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	-0.51
CADD	Benign	8.0
DANN	Benign	0.96

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: rs61737724; hg19: chr4-83350763; COSMIC: COSV55023661; COSMIC: COSV55023661;