4-82358578-C-T

Variant names:

• chr4-82358578-C-T
• rs35798371
• NM_031370.3:c.621+81G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_031370.3(HNRNPD):​c.621+81G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0893 in 1,292,492 control chromosomes in the GnomAD database, including 5,827 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (464 hom., cov: 32)
  • Exomes 𝑓: 0.092 (5363 hom.)
• Consequence: HNRNPD NM_031370.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.832

Genes affected

HNRNPD (HGNC:5036): (heterogeneous nuclear ribonucleoprotein D) This gene belongs to the subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are nucleic acid 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 repeats of quasi-RRM domains that bind to RNAs. It localizes to both the nucleus and the cytoplasm. This protein is implicated in the regulation of mRNA stability. Alternative splicing of this gene results in four transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 4-82358578-C-T is Benign according to our data. Variant chr4-82358578-C-T is described in ClinVar as [Benign]. Clinvar id is 1277518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNRNPD	NM_031370.3	c.621+81G>A		intron_variant	Intron 4 of 8	ENST00000313899.12	NP_112738.1
HNRNPD	NM_031369.3	c.564+81G>A		intron_variant	Intron 3 of 7		NP_112737.1
HNRNPD	NM_002138.4	c.621+81G>A		intron_variant	Intron 4 of 7		NP_002129.2
HNRNPD	NM_001003810.2	c.564+81G>A		intron_variant	Intron 3 of 6		NP_001003810.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNRNPD	ENST00000313899.12	c.621+81G>A		intron_variant	Intron 4 of 8	1	NM_031370.3	ENSP00000313199.7

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10567 AN: 152122 Hom.: 464 Cov.: 32

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.0579

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.0401

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0843

GnomAD4 exome AF: 0.0919 AC: 104827 AN: 1140252 Hom.: 5363 Cov.: 15 AF XY: 0.0906 AC XY: 51939 AN XY: 573128

African (AFR) AF: 0.0160 AC: 413 AN: 25752

American (AMR) AF: 0.0462 AC: 1378 AN: 29838

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 1873 AN: 19582

East Asian (EAS) AF: 0.0264 AC: 997 AN: 37766

South Asian (SAS) AF: 0.0381 AC: 2552 AN: 67066

European-Finnish (FIN) AF: 0.0601 AC: 2980 AN: 49620

Middle Eastern (MID) AF: 0.0790 AC: 259 AN: 3280

European-Non Finnish (NFE) AF: 0.105 AC: 90128 AN: 858462

Other (OTH) AF: 0.0869 AC: 4247 AN: 48886

GnomAD4 genome AF: 0.0694 AC: 10564 AN: 152240 Hom.: 464 Cov.: 32 AF XY: 0.0669 AC XY: 4979 AN XY: 74428

African (AFR) AF: 0.0178 AC: 738 AN: 41554

American (AMR) AF: 0.0578 AC: 884 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3468

East Asian (EAS) AF: 0.0297 AC: 154 AN: 5190

South Asian (SAS) AF: 0.0401 AC: 194 AN: 4832

European-Finnish (FIN) AF: 0.0634 AC: 672 AN: 10592

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7196 AN: 68004

Other (OTH) AF: 0.0834 AC: 176 AN: 2110

Alfa AF: 0.0892 Hom.: 149

Bravo AF: 0.0687

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.69
DANN	Benign	0.52
PhyloP100		-0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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

Publications

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Other links and lift over

dbSNP: rs35798371; hg19: chr4-83279731;