rs6826022

Variant names:

• chr4-82427825-T-C
• rs6826022
• NM_031372.4:c.774+193A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_031372.4(HNRNPDL):​c.774+193A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 152,138 control chromosomes in the GnomAD database, including 9,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.33 (9817 hom., cov: 33)
• Consequence: HNRNPDL NM_031372.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85
• Publications: 7 publications found

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]

HNRNPDL Gene-Disease associations (from GenCC):

• autosomal dominant limb-girdle muscular dystrophy type 1G

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• muscular dystrophy, limb-girdle, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-82427825-T-C is Benign according to our data. Variant chr4-82427825-T-C is described in ClinVar as Benign. ClinVar VariationId is 1222212.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPDL	NM_031372.4	c.774+193A>G		intron_variant	Intron 3 of 7	ENST00000295470.10	NP_112740.1
HNRNPDL	NM_001207000.1	c.774+193A>G		intron_variant	Intron 3 of 6		NP_001193929.1
HNRNPDL	NR_003249.2	n.1309+193A>G		intron_variant	Intron 3 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPDL	ENST00000295470.10	c.774+193A>G		intron_variant	Intron 3 of 7	1	NM_031372.4	ENSP00000295470.5

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50291 AN: 152020 Hom.: 9812 Cov.: 33

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.467

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.387

Gnomad OTH AF: 0.366

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.331 AC: 50320 AN: 152138 Hom.: 9817 Cov.: 33 AF XY: 0.339 AC XY: 25183 AN XY: 74350

African (AFR) AF: 0.129 AC: 5366 AN: 41534

American (AMR) AF: 0.480 AC: 7332 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.467 AC: 1618 AN: 3468

East Asian (EAS) AF: 0.212 AC: 1100 AN: 5180

South Asian (SAS) AF: 0.549 AC: 2650 AN: 4826

European-Finnish (FIN) AF: 0.443 AC: 4670 AN: 10540

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.387 AC: 26328 AN: 67980

Other (OTH) AF: 0.365 AC: 772 AN: 2116

Alfa AF: 0.381 Hom.: 22197

Bravo AF: 0.319

Asia WGS AF: 0.387 AC: 1343 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.25
DANN	Benign	0.57
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6826022; hg19: chr4-83348978;